Methods and devices for orthovoltage ocular radiotherapy and treatment planning

ABSTRACT

A method, code and system for planning the treatment a lesion on or adjacent to the retina of an eye of a patient are disclosed. There is first established at least two beam paths along which x-radiation is to be directed at the retinal lesion. Based on the known spectral and intensity characteristics of the beam, a total treatment time for irradiation along each beam paths is determined. From the coordinates of the optic nerve in the aligned eye position, there is determined the extent and duration of eye movement away from the aligned patient-eye position in a direction that moves the patient&#39;s optic nerve toward the irradiation beam that will be allowed during treatment, while still maintaining the radiation dose at the patient optic nerve below a predetermined dose level.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/887,419 filed Sep. 11, 2010, which is a continuation of U.S. patentapplication Ser. No. 12/262,031 filed Oct. 30, 2008, now U.S. Pat. No.7,801,271, which claims the benefit of priority of U.S. Application Nos.61/101,013 filed Sep. 29, 2008; 61/093,092 filed Aug. 29, 2008; and61/076,128 filed Jun. 26, 2008. U.S. patent application Ser. No.12/887,419 is also a continuation-in-part of U.S. application Ser. No.12/103,534 filed Apr. 15, 2008, now U.S. Pat. No. 8,363,783, whichclaims benefit of priority to U.S. Application Nos. 61/016,472 filedDec. 23, 2007; and 61/020,655 filed Jan. 11, 2008; U.S. application Ser.No. 12/103,534 is also a continuation-in-part of U.S. application Ser.No. 12/100,398 filed Apr. 9, 2008, now U.S. Pat. No. 7,693,260, U.S.application Ser. No. 12/103,534 is also a continuation-in-part of U.S.application Ser. No. 12/027,083 filed Feb. 6, 2008, now pending. U.S.application Ser. No. 12/103,534 is also a continuation-in-part of U.S.application Ser. No. 12/027,094 filed Feb. 6, 2008, now pending. U.S.application Ser. No. 12/103,534 is also a continuation-in-part of U.S.application Ser. No. 12/027,069 filed Feb. 6, 2008, now pending; theentirety of each of which is incorporated herein by reference.

The following U.S. patent applications are incorporated herein byreference: Ser. No. 11/873,386 filed Oct. 16, 2007; Ser. No. 11/833,939filed Aug. 3, 2007; Ser. No. 11/879,901 filed Jul. 18, 2007; Ser. No.11/879,843 filed Jul. 18, 2007; No. 60/933,220 filed Jun. 4, 2007; No.60/922,741 filed Apr. 9, 2007; No. 60/869,872 filed Dec. 13, 2006; No.60/862,210 filed Oct. 19, 2006; No. 60/862,044 filed Oct. 18, 2006; andNo. 60/829,676 filed Oct. 16, 2006.

BACKGROUND

1. Field of the Inventions

This disclosure relates to the using targeted photon energy for thetreatment of disorders of the human and animal body. In particular, thepresent disclosure pertain to systems and methods for performing animage-guided low-energy X-ray therapy procedure on a patient's eye, tosystems for planning and controlling such treatments, and to eyealignment-stabilization systems useful in ophthalmologic procedures.

2. Description of the Related Art

Macular degeneration is a condition where the light-sensing cells of themacula, a near-center portion of the retina of the human eye,malfunction and slowly cease to work. Macular degeneration is theleading cause of central vision loss in people over the age of fiftyyears. Clinical and histologic evidence indicates that maculardegeneration is in part caused by or results in an inflammatory processthat ultimately causes destruction of the retina. The inflammatoryprocess can result in direct destruction of the retina or destructionvia formation of neovascular membranes which leak fluid and blood intothe retina, quickly leading to scarring.

Many treatments for macular degeneration are aimed at stopping theneovascular (or “wet”) form of macular degeneration rather thangeographic atrophy, or the “dry” form of Age-related MacularDegeneration (AMD). All wet AMD begins as dry AMD. Indeed, the currenttrend in advanced ophthalmic imaging is that wet AMD is being identifiedprior to loss of visual acuity. Treatments for macular degenerationinclude the use of medication injected directly into the eye (Anti-VEGFtherapy) and laser therapy in combination with a targeting drug(photodynamic therapy); other treatments include brachytherapy (i.e.,the local application of a material which generates beta-radiation).

Accurate alignment of a subject's eye is important in a number ofsituations. For example, when taking certain types of eye measurements,it is critical to know that the eye is in a particular referenceposition. When measuring the cornea of a patient's eye beforetherapeutic treatment, it can be important to repeat those measurementsafter the treatment to determine how much, if any, the treatment hasaffected the measurements. In order to accomplish this, one must ensurethat the eye alignment is in the same position each time the particularmeasurements are made. Otherwise, the difference in data from before andafter the treatment might be due to a change in eye alignment ratherthan the treatment.

A number of treatment and surgery procedures, typically involvingirradiating one or more selected targets in the eye, require a patient'seye to be stabilized or positioned prior to and/or during treatment. Forexample, refractive laser surgery involves ablating corneal tissue ofthe eye with an ultra-fast, ultra-short pulse duration laser beam, tocorrect refractive errors in a patient's eye. As such, the patient's eyemust be stabilized, and either the laser system must be properly andprecisely aligned with the patient's eye, or the patient's eye must beproperly and precisely aligned with the laser system. The eye ispredisposed to saccades, which are fast, involuntary movements of smallmagnitude. A patient may voluntarily shift their gaze during surgery,and furthermore, eye position stability is affected by the patient'sheartbeat and other physiological factors.

In order to achieve the goal of maximizing results while minimizingrisks to the patient during such eye treatment, it is important toeliminate, or at least significantly reduce, as many system errors aspossible. This includes the improper alignment of the patient's eyerelative to the treatment system. Alignment errors may result fromeither a misconfiguration of the system, or from the patient'sinteraction with the system. Insofar as patient/system interaction isconcerned, any voluntary or involuntary movement of the patient's eyeduring treatment can significantly alter the alignment of the eyerelative to the treatment system. It is necessary, therefore, to holdthe eye of the patient stationary during these procedures.

In addition, there is a need to control the distribution of radiationabsorption by ocular structures during treatment, such as to assure anadequate dosage to a lesion being treated, and to avoid damagingcollateral structures by stray radiation.

SUMMARY

Further description may be found in the priority applications, inparticular Ser. No. 12/103,534 filed Apr. 15, 2008; Ser. No. 12/027,069filed Feb. 1, 2008; and Ser. No. 12/100,398 filed Apr. 9, 2008; each ofwhich is incorporated by reference. An embodiment having aspects of theinvention comprises an eye-contact device (eye-guide) for securing apatient eye at a selected position, such as may be used cooperativelywith an ocular stabilization and alignment device, such as is describedin the co-invented priority applications, particularly Ser. No.12/103,534 filed Apr. 15, 2008 and Ser. No. 12/027,083 filed Feb. 1,2008; each of which is incorporated herein by reference.

A treatment method embodiment having aspects of the invention includestreating a lesion on or adjacent to the retina of an eye of a patient(which by be referred to regardless of histology as a “retinal lesion”)by directing collimated X-radiation at the lesion in a patient's eye.The method comprises the steps of: (a) based on an aligned patient-eyeposition, establishing at least two treatment beam paths directed from asource of a collimated x-radiation beam through the patient's sclerabeyond the limbus and directed at the retinal lesion; (b) determining,based on the known spectral and intensity characteristics of the sourcebeam along the established beam paths and from the coordinates of thelesion in the aligned patient-eye position, a total treatment time forirradiation along the beam paths that is effective to produce a desiredradiation dose at the lesion of the patient's eye; and (c) determining,based on the known spectral and intensity characteristics of the sourcebeam along the established beam paths, and from the coordinates of theoptic nerve in the aligned eye position, the extent and duration of eyemovement away from the aligned patient-eye position in a direction thatmoves the patient's optic nerve toward the irradiation beam that will beallowed during treatment, while still maintaining the radiation dose atthe patient optic nerve below a predetermined dose level.

The treatment method may further provide that the retinal lesion to betreated includes one of macular degeneration; a drusen, a tumor or avascular abnormality, and step (c) includes determining the coordinatesof the lesion and the optic nerve in an external coordinate system. Inparticular embodiments, the retinal lesion to be treated includesmacular degeneration, and step (c) includes determining the coordinatesof the macula and the optic nerve in an external coordinate system.

The treatment method may further provide that the aligned patient-eyeposition places the optical axis of the eye in alignment with an axisnormal to the cornea of the eye with the patient looking straight ahead.Step (a) may include the steps of determining, for the source ofcollimated x-radiation beam; (i) a beam-source collimator configurationthat is based on an X-ray emission source-to-target distance, acollimator exit aperture-to-body surface distance, an emission or anodesource size, and a collimator exit aperture size, and that is calculatedto provide an X-ray beam-spot at the retina having a diameter orcharacteristic dimension to the 80% isodose of less than about 8 mm, anda penumbra width between the 80% isodose and the 20% isodose of lessthan about 40% of the beam-spot diameter or beam spot characteristicdimension; and (ii) a maximum photon energy and a beam filtrationconfiguration to provide a maximum photon energy between 25-150 keV.

The treatment method may further provide that the maximum photon energyand a beam filtration are such as to provide a sclera surface-to-retinatarget dose ratio for the beam of less than N:1, where N is the numberof established beams. Step (a) may include establishing at least threebeam paths having a total beam angular divergence of between 20-60degrees. Step (a) may include establishing a series of beam pathsproduced a continuously moving the beam source along an arcuate path.

The treatment method may further provide that step (b) includes (i)measuring an ocular dimension of the patient's eye; (ii) scaling a modelof the eye that includes the coordinates of retinal features, includingthe macula and optic nerve, and a virtual ocular medium to the oculardimension measured in step, and (iii) determining from the knowndistance of travel of the beam within the model along each path, andfrom the virtual ocular medium through which the beam travels, the doseof radiation from the source that needs to be delivered along each path,to produce the desired radiation dose at the macula of the patient'seye.

The treatment method may further provide that step (c) includesdetermining, from the known distance of travel of the beam within themodel along each beam path, and from the virtual ocular medium throughwhich the beam travels, the dose of radiation that is received by theoptic nerve as a function of eye movement in a direction that moves thepatient's optic nerve toward the irradiation beam.

A machine-readable code embodiment having aspects of the invention canoperate on a computer to execute machine-readable instructions forperforming the steps in a treatment planning method for treating alesion on or adjacent to the retina of an eye of a patient (“retinallesion”), by directing collimated X-radiation beams at the lesion in apatient's eye, the code providing instructions for steps comprising: (a)based on an aligned patient-eye position, establishing at least twotreatment beam paths directed from a source of a collimated x-radiationbeam through the patient's sclera beyond the limbus and directed at thelesion; (b) determining, based on the known spectral and intensitycharacteristics of the source beam along the established beam paths andfrom the coordinates of the ocular lesion in the aligned patient-eyeposition, a total treatment time for irradiation along the beam pathsthat is effective to produce a desired radiation dose at the ocularlesion of the patient's eye; and (c) determining, based on the knownspectral and intensity characteristics of the source beam along theestablished beam paths, and from the coordinates of the optic nerve inthe aligned eye position, the extent and duration of eye movement awayfrom the aligned patient-eye position in a direction that moves thepatient's optic nerve toward the irradiation beam that will be allowedduring treatment, while still maintaining the radiation dose at thepatient optic nerve below a predetermined dose level.

The code embodiment may provide that the retinal lesion to be treatedincludes one of macular degeneration; a drusen, a tumor or a vascularabnormality; and that step (c) includes determining the coordinates ofthe lesion and the optic nerve in an external coordinate system. Inparticular embodiments the retinal lesion to be treated includes maculardegeneration, and step (c) includes determining the coordinates of themacula and the optic nerve in an external coordinate system.

The code may be operable, in performing step (a), to determine, for thesource of collimated x-radiation beam, (i) a beam-source collimatorconfiguration that is based on an X-ray emission source-to-targetdistance, a collimator exit aperture-to-body surface distance, anemission or anode source size, and a collimator exit aperture size, andthat is calculated to provide an X-ray beam-spot at the retina having adiameter or characteristic dimension to the 80% isodose of less thanabout 8 mm, and a penumbra width between the 80% isodose and the 20%isodose of less than about 40% of the beam-spot diameter or beam spotcharacteristic dimension; and (ii) a maximum photon energy and a beamfiltration configuration to provide a maximum photon energy between25-150 keV.

The code may further be operable, in performing step (b) and based on ameasured ocular dimension of the patient's eye, to (i) scale a model ofthe eye that includes the coordinates of retinal features, including themacula and optic nerve, and a virtual ocular medium to the oculardimension measured in step, and (ii) determining from the known distanceof travel of the beam within the model along each path, and from thevirtual ocular medium through which the beam travels, the dose ofradiation from the source that needs to be delivered along each path, toproduce the desired radiation dose at the macula of the patient's eye.

A treatment planning system embodiment having aspects of the inventionincludes planning a treatment for a lesion on or adjacent to the retinaof an eye of a patient (“retinal lesion”), the treatment carried out bydirecting a collimated X-radiation beam at the lesion in a patient'seye. The system comprises: (a) a device for aligning the patient eye;(b) a processor operable to receive coordinates of the aligned eye in anexternal coordinate system, and which stores information effective fordetermining, from the received coordinates, coordinates of the lesionand optic nerve in the patient eye; and (c) machine-readable code whichoperates on the processor to execute machine-readable instructions. Thecode provides machine-readable instructions which may be executed toperform the steps of: (i) based on the an aligned patient-eyecoordinates, establishing at least two treatment beam paths directedfrom a source of a collimated x-radiation beam through the patient'ssclera beyond the limbus and directed at the lesion; (ii) determining,based on the known spectral and intensity characteristics of the sourcebeam along the established beam paths and from the coordinates of thelesion in the aligned patient-eye position, a total treatment time forirradiation along the beam paths that is effective to produce a desiredradiation dose at the lesion of the patient's eye; and (iii)determining, based on the known spectral and intensity characteristicsof the source beam along the established beam paths, and from thecoordinates of the optic nerve in the aligned eye position, the extentand duration of eye movement away from the aligned patient-eye positionin a direction that moves the patient's optic nerve toward theirradiation beam that will be allowed during treatment, while stillmaintaining the radiation dose at the patient optic nerve below apredetermined dose level.

The treatment planning system embodiments may further provide that theretinal lesion to be treated includes one of macular degeneration; adrusen, a retinal tumor or a retinal vascular abnormality; and step(c)(iii) includes determining the coordinates of the lesion and theoptic nerve in an external coordinate system. In particular embodiments.the retinal lesion to be treated includes macular degeneration, and step(c)(iii) includes determining the coordinates of the macula and theoptic nerve in an external coordinate system.

The treatment planning system embodiments may further provide that thecode may be operable, in performing step (c), to determine, for thesource of collimated x-radiation beam, (i) a beam-source collimatorconfiguration that is based on an X-ray emission source-to-targetdistance, a collimator exit aperture-to-body surface distance, anemission or anode source size, and a collimator exit aperture size, andthat is calculated to provide an X-ray beam-spot at the retina having adiameter or characteristic dimension to the 80% isodose of less thanabout 8 mm, and a penumbra width between the 80% isodose and the 20%isodose of less than about 40% of the beam-spot diameter or beam spotcharacteristic dimension; and (ii) a maximum photon energy and a beamfiltration configuration to provide a maximum photon energy between25-150 keV. The code may also be operable, in performing step (b) andbased on a measured ocular dimension of the patient's eye, to (i) scalea model of the eye that includes the coordinates of retinal features,including the macula and optic nerve, and a virtual ocular medium to theocular dimension measured in step, and (ii) determining from the knowndistance of travel of the beam within the model along each path, andfrom the virtual ocular medium through which the beam travels, the doseof radiation from the source that needs to be delivered along each path,to produce the desired radiation dose at the macula of the patient'seye.

A treatment planning method embodiment having aspects of the inventionincludes treating macular degeneration in a patient according to atreatment plan by directing collimated X-radiation at the macula in apatient's eye. The method comprises: (a) measuring an ocular dimensionof the patient's eye, (b) scaling a model of the eye that includes thecoordinates of retinal features, including the macula, and a virtualocular medium to the ocular dimension measured in step (a), (c)establishing at least two treatment axes along which a collimated beamof X-radiation will be directed from an external radiation source at themacula in the eye model, and (d) determining from the known distance oftravel of the beam within the model along each treatment axis, and fromthe virtual ocular medium through which the beam travels, the dose ofradiation from the source that needs to be delivered along eachtreatment axis, to produce a predetermined total radiation dose at themacula of the patient's eye.

The method may further provide that step (a) includes measuring along anocular axis, the ocular length of the patient's eye between the corneaand retina of the eye, and step (b) includes scaling the ocular lengthof the model to the patient's measured ocular length. Step (c) mayinclude establishing treatment axes directed through the sclera andconverging at the macula in the eye model, and having a totalbeam-to-beam angular divergence of between 20-60 degrees. The eye modelmay include coordinates of the optic nerve at the retina. The dose ofradiation determined in step (d) may be determined as specified beamintensity over a given irradiation period, and step (d) may furtherinclude determining a permitted extent of eye movement over theirradiation period that maintains the radiation dose received at thepatient optic nerve below a predetermined level.

A machine-readable code embodiment having aspects of the invention canoperate on a computer to execute machine-readable instructions forperforming the steps in a treatment planning method for treating maculardegeneration in a patient by directing collimated X-radiation beams atthe macula in a patient's eye, the code providing instructions for stepscomprising: (a) scaling a model of the eye that represents retinalfeatures, including the macula, and a virtual ocular medium to apatient-eye ocular dimension supplied as input; (b) establishing atleast two treatment axes along which a collimated beam of X-radiationwill be directed from an external radiation source at the macula in theeye model; and (c) determining from the known distance of travel of thebeam within the model along each treatment axis, and from the virtualocular medium through which the beam travels, the dose of radiation fromthe source that needs to be delivered along each treatment axis, toproduce a predetermined total radiation dose at the macula of thepatient's eye.

An method embodiment having aspects of the invention for treating apatient with a radiation beam from a orthovoltage X-ray emission sourceto a treatment target region on or adjacent to the retina, comprises thesteps of:

(a) determining a radiation treatment plan, the plan including one ormore of: (i) determining one or more distinct X-ray beam pathsintersecting both the sclera surface and the target region, each beampath configured to substantially avoid both of the lens and the opticnerve of the treated eye; (ii) providing one or more X-ray beamcollimators having a configuration including an X-ray emissionsource-to-target distance, a collimator exit aperture-to-body surfacedistance, an emission or anode source size, and a collimator exitaperture size, the collimator providing an X-ray beam having a X-raybeam-spot at the retina having a diameter or characteristic dimension tothe 80% isodose of less than about 8 mm, and a penumbra width betweenthe 80% isodose and the 20% isodose of less than about 40% of thebeam-spot diameter or beam spot characteristic dimension; (iii)determining one or both of an X-ray source maximum photon energy and abeam filtration configuration configured to provide a collimated beamspectrum such that, as administered on the X-ray beam path, the maximumphoton energy is less than about 300 keV;

(b) determining one or more of an X-ray beam duration and/or X-ray fluxintensity level so as to provide a selected absorbed radiation dose tothe retina target;

(c) aiming the collimator of step (a)(ii) to align with at least onebeam path determined treating the patient according to the radiationtreatment plan; and

(d) emitting the calculated X-ray beam duration and/or flux level alongeach distinct X-ray beam path, so as to administer the selected beamradiation absorbed dose to the retina target.

In one alternative, step (b) may be based at least in part on one ormore of: (i) at least one measurement of patient-specific eye anatomy;(ii) a selected sclera surface-to-retina target dose ratio for eachX-ray beam; and (iii) the number of distinct X-ray beam paths. Themethod embodiment may further include the steps of: (e) engaging thetreated eye during irradiation with an eye contact member; and (f)supporting and/or controlling the eye contact member so as tosubstantially reduce eye motion during radiation treatment. Optionally,the method may include (g) tracking at least one motion of the treatedeye during irradiation; (h) determining at least one alignment of anX-ray beam path with the retinal target during irradiation based ontracked eye motion so as to determine an alignment error relative to theplanned beam path; and (i) in the event that a selected threshold oferror is determined, either or both of interrupting or discontinuingirradiation of the treated eye; or re-aligning the X-ray beam path withthe retinal target.

A treatment method embodiment having aspects of the invention includestreating a patient with external radiation beam from a radiation source,the radiation beam emitted so as to propagate along an tissue path toreach a target tissue region within the patient's body, the treatmentcarried out according to a radiotherapy treatment plan anatomicallyspecifying the tissue path. The method comprises the steps of: (a)selecting one or more input parameters (P₁, P₂ . . . P_(i),), the inputparameters selected from human anatomical measurements, other humanmeasurements, and other person-specific characteristics; (b)characterizing variation with respect to the selected parameters in ahuman population which includes the patient, the variation correlatedwith the tissue path length (PL) for the radiotherapy treatment plan;(d) determining a mathematical function and/or calculation algorithmeffectively expressing a relationship between the selected parametersand the tissue path length (PL=f(P₁, P₂ . . . P_(i)); (e) determiningvalues of the selected parameters (P₁, P₂ . . . P_(i),) for the patient;(f) using the mathematical function and/or calculation algorithm,determining PL for the patient (PL₀); (g) modifying or adjusting one ormore aspects of the radiotherapy treatment plan based on the determinedvalue PL₀; and (h) treating the patient according to the modified oradjusted treatment plan.

The method may further provide that the modified or adjusted aspects ofthe treatment plan include one or more of beam duration, total radiationdose, beam spectral energy, beam filtration, beam collimation geometry,and beam orientation. The radiation beam may include an orthovoltageX-ray beam having a maximum photon energy of less than 500 keV. Thetarget tissue region within the patient's body may include tissue withinan eye of the patient, such as a portion of the retina, and theanatomical tissue path may include a path from an entry point on thesclera surface propagating through the eye to the target region. Theselected parameters may include an eye axial length, e.g., as determinedby an ultrasonic A-scan measurement.

A treatment method embodiment having aspects of the invention includestreating an ocular lesion in a patient by directing collimatedX-radiation at the lesion in a patient's eye. The method comprises thesteps of: (a) based on an aligned patient-eye position, establishing atleast two treatment beam paths directed from a source of a collimatedX-radiation beam through the surface of the patient's e and directed atocular lesion; (b) determining, based on the known spectral andintensity characteristics of the source beam along the established beampaths and from the coordinates of the lesion in the aligned patient-eyeposition, a total treatment time for irradiation along the beam pathsthat is effective to produce a desired radiation dose at the lesion ofthe patient's eye; and (c) determining, based on the known spectral andintensity characteristics of the source beam along the established beampaths, and from the coordinates of a selected radiation sensitivestructure in the eye, in the aligned eye position, the extent andduration of eye movement away from the aligned patient-eye position in adirection that moves the patient's radiation-sensitive structure towardthe irradiation beam that will be allowed during treatment, while stillmaintaining the radiation dose at the patient radiation-sensitivestructure below a predetermined dose level.

The method may further provide that (i) the ocular lesion to be treatedincludes one of a pterygium, a vascular malformation; an ocular tumor;an ocular premalignant lesion; a choroidal hemangioma; an ocularmetastasis; a nervus; a conjunctival tumor; an eyelid tumor; an orbitaltumor, and tissue associated with glaucoma; and (ii) theradiation-sensitive structure includes one of the lens of the eye, thecornea and the optic nerve.

These and other objects and features of the invention will be more fullyappreciated when the following detailed description of the invention isread in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

The FIGURES and the associated descriptions are provided to illustrateembodiments of the disclosure and not to limit the scope of thedisclosure. Throughout the figures, reference numbers are reused toindicate correspondence between referenced elements. The FIGURES are insimplified form and are not necessarily precise in scale. In referenceto the disclosure herein, for purposes of convenience and clarity only,directional terms, such as top, bottom, left, right, up, down, over,above, below, beneath, rear, and front are used with respect to theaccompanying figures. Such directional terms are not to be construed aslimiting the scope of the invention in any manner. Likewise, referencenumerals in the figures are for purposes of convenience and arediscussed in the description in the context of the figures in which theyappear. Generally, the same reference numeral is used to denote ahomologous or similar element in more than one figure. However, in somecases, a particular structure or element may be referred to in onefigure by one reference numeral, and the same or substantially similarstructure or element may be referred to in another figure by a differentreference numeral.

The FIGURES include the following:

A. Radiotherapy Treatment Parameters and Planning

FIG. 1 is a cross-sectional view representing a CT scan of a portion ofa patient's head, depicting a prior art ocular radiotherapy procedure,and in comparison depicts a orthovoltage ocular radiotherapy procedureaccording to methods and devices having aspects of the invention herein.

FIG. 2 is a cross-sectional view of a region of a posterior eye,depicting a prior art proton beam treatment.

FIG. 3 shows a schematic overview of an embodiment of a treatmentplanning system and method having aspects of the invention.

FIGS. 4A-C illustrate the relation between the treatment planning systemand eye model with various components of radiotherapy system havingaspects of the invention in the treatment of eye.

FIG. 5 is a schematic chart illustrating a method of clinicalapplication of a radiotherapy system having aspects of the invention.

FIG. 6 depicts an exemplary clinical flow method involving theradiotherapy device in accordance with treatment planning embodimentsdescribed herein.

FIG. 7 a cross-sectional view of an eye, shown in association with anembodiment of a radiotherapy system having aspects of the invention.

FIG. 8 depicts an exemplary set of orthovoltage X-ray spectra showing atrend of characteristic photon energy distribution with increasingsource tube voltage.

FIG. 9 depicts an set of 80 kVp X-ray spectra showing a trend of photonenergy distribution with increasing thickness of Al filter material.

FIG. 10 is a plot showing the depth propagation/absorbs ion curve for anexemplary treatment beam penetrating simulated tissue

FIG. 11 is a plot showing the effect of a range of X-ray tube potentialsand two different filter thickness on depth-dose ratio measured at atypical retinal depth.

FIG. 12 depicts an exemplary sequence of spectra corresponding to thepropagation of a radiotherapy beam through system filters and simulatedpatient tissue anatomy.

FIG. 13 illustrates a representative geometric model of the eye used formodeling purposes, showing representative radiation beam angles withrespect to an anterior surface and geometric axis of the eye.

FIG. 14 depicts results of Monte Carlo simulations performed to analyzethe effect of various treatment regimes on the various structures of theeye.

FIGS. 15-17D depict the results of a radiation modeling study of varyingoptic nerve angles with respect to the posterior sclera, the geometry ofthe beam cases of the study, and the anatomic geometry of differentoptic nerve cases studied.

FIG. 18 depicts an eye in cross section, further showing aspects of ananatomical targeting method for radiotherapy.

FIG. 19A is a schematic view of a fundus image on a patient's retinashowing one example of a treatment plan for AMD.

FIG. 19B is a schematic view of an virtual eye model including a medicalimage registered with eye anatomy.

FIG. 20 schematically depicts an example of a virtual or phantom modelof a human eye which is included in treatment planning and controlembodiments having aspects of the invention.

FIG. 21 schematically depicts a virtual or phantom model of an X-raysource and collimator system associated with a simplified anatomicalrepresentation of an eye being treated.

FIGS. 22A-22D schematically depicts a model similar to that of FIG. 21,comparing graphically the effect of four different examples of X-raysource anode sizes on target beam spot and penumbra for a constantcollimator configuration.

FIG. 23 is a plot showing the results of a Monte Carlo computationalsimulation of example configurations generally similar to those shown inFIG. 22.

FIGS. 24A and 24B depict the results of a single collimated x-ray beam2600, both at the collimator aperture and after it has penetratedthrough about 20 mm of solid water phantom material.

FIG. 24C shows a plot of penumbra from measurements within an x-raydetection films at a macular and retinal locations of a solid water eyemodel.

FIGS. 25A-25D schematically depicts a model similar to that of FIGS.22A-D, comparing the same four different examples of source anode sizes,but for collimator configurations having apertures sized to produce aconstant central beam-spot size at the target plane.

FIGS. 26A-26C schematically depicts a model similar to that of FIG. 21,comparing graphically the effect of three different examples ofanode-to-target distance on penumbra, for collimator configurationshaving apertures sized to produce a constant central beam-spot size atthe target plane.

FIGS. 27A-27C schematically depicts a model similar to that of FIG. 21,comparing graphically the effect of three different examples ofcollimator exit plane-to-target distance on penumbra, for sourceconfigurations having constant anode-to-target distances, and aperturessized to produce a constant central beam-spot size at the target plane.

FIG. 28 is cross-sectional diagram of a variable length collimatorhaving an extensible support for the exit plane aperture, shown in thisexample in the form of a “zoom-lens”-like mounting of an aperture disk.

FIG. 29A is a plot showing the results of a Monte Carlo computationalsimulation for absorption of X-ray energy in a configuration generallysimilar to that shown in FIG. 12.

FIG. 29B shows a plot of measured dose intensity at retinal depth for anX-ray/collimator configuration comparable to that of FIG. 30B.

FIG. 30A is a frontal view of an eye as seen aligned with a systemreference axis, and depicting stereotactic X-ray treatment beamgeometry,

FIG. 30B depicts results of a procedure in which three beams werefocused on the back of an phantom eye model using a robotic system, andrepresents overlapping x-rays at a target site.

FIG. 30C-D are plots illustrating a stereotactic 3-beam dose map ofretinal dose measured by radiometry on a phantom eye or mannequin.

FIG. 31A shows a typical example of the mapping eye geometry usinglaser-scanner measurements on cadaver eyes.

FIG. 31B is a plot showing the relationship between tissue path lengthand axial length from measurements such as are shown in FIG. 31A.

FIG. 31C is a plot showing for each of seven example cadaver eyes, theA-scan derived axial length, together with the laser-scanner value oftissue path length, and a calculated tissue path length according to anexample linear formula.

FIG. 31D is a plot depicting the relation between measured patientanatomy and tissue path length for an exemplary radiotherapy treatmentplan.

FIG. 32 is a plot depicting the relation between the beam tissue pathlength and the duration of beam emission required to deliver a plannedtarget dose for an exemplary embodiment of a X-ray treatment system.

B. Radiotherapy Treatment Delivery

FIGS. 33A and 33B is a perspective view and plan layout of an exemplaryembodiment of an X-ray treatment system having aspects of the invention,for treating ocular diseases.

FIG. 34 shows a patient's head including cross-section of an eye in thevertical plane of symmetry of the eye, shown in association withembodiments of an imaging system and an X-ray source assembly havingaspects of the invention.

FIG. 35 is a perspective detail view of the system components shown inFIG. 31 together with portions of an automated positioning system havingaspects of the invention.

FIG. 36 is a longitudinal cross-sectional view of the collimator and aportion of X-ray tube.

FIG. 37 is a perspective illustration of an embodiment of a positioningsystem having aspects of the invention.

FIG. 38 is a perspective detail showing collimator rotational motion asmoving in one operational alternative of the positioning system of FIG.37.

FIG. 39 illustrates a top view of one embodiment of a system forcontrollably positioning and/or stabilizing the eye of a subject fortherapeutic treatment.

FIGS. 40A-B illustrate perspective views of the contact device or eyeguide having aspects of the invention in various cases of alignment witha system axis.

FIGS. 41A-B illustrate top views of an embodiment of a system forengaging the eye of a subject.

FIG. 42A-D depicts perspective views of the contact device with thecontrol arm attached having aspects of the invention.

FIGS. 43A-E are a flow chart and related schematic drawings whichillustrate an exemplary method of eye alignment and treatment employingan eye-guide device having aspects of the invention.

FIGS. 44A-B depicts a method of confirming an embodiment of aradiotherapy treatment plan having aspects of the invention usingradiographic measurements on a cadaver eye

FIGS. 45A-B depicts one embodiment of an eye-guide having aspects of theinvention engaged with an eye having one embodiment of an eyelidretractor.

FIGS. 46A-B depicts an alternative embodiment of an eye-guide havingaspects of the invention engaged with an eye having an alternativeembodiment of an eyelid retractor.

FIG. 47A schematically illustrate a eye-guide device for use in a eyestabilizing system having aspects of the invention having a number ofalternative fiducial configurations.

FIGS. 47B1-I schematically illustrate a eye-guide device for use in aeye stabilizing system having aspects of the invention, and havingpatterned fiducials, and a method of determining orientation by imagerecognition.

FIGS. 48A-F illustrate an eye-guide device having a pattern offiducials, the guide for use in a eye stabilizing system having aspectsof the invention, shown in contact with an eye and depicting the methodof determining alignment.

FIGS. 49A-E are plots showing eye movements experimentally measured withan embodiment of a system for controllably positioning and/orstabilizing the eye of a subject.

FIGS. 50 and 51A,B are flowcharts illustrating eye-guide fiducial imagedata acquisition and processing methods.

FIGS. 52A-B are two views plan view of an eye-guide included in a eyestabilizing system having aspects of the invention, shown in contactwith an eye during X-ray treatment, illustrating the effect on retinalposition of motion of the eye in the system Z direction.

FIGS. 53A-B are two views plan view of an eye-guide having aspects ofthe invention in contact with an eye during X-ray treatment,illustrating the effect on retinal position of rotational motion of theeye.

FIGS. 54A-B are views illustrating from a frontal perspective the motionshown in FIGS. 53A-B.

FIG. 54C is a flow chart illustrating an exemplary planning methodincluding determining a safe or allowable eye movement threshold to bepermitted during treatment.

FIG. 54D, view (1)-(3) illustrate the relation of retinal motion toradiation dose distribution.

C. Alternative Radiation Beam Treatment.

FIGS. 55A-D are views illustrating an alternative methods and deviceshaving aspects of the invention including micro-fractionated beamsdirected through the cornea to a retinal target.

FIGS. 56A-E are views illustrating an alternative methods and deviceshaving aspects of the invention including a plurality of narrowlycollimated beams directed through the cornea to a retinal target.

FIGS. 57A-H are views illustrating an alternative methods and deviceshaving aspects of the invention including a narrowly collimated beamsdirected via continuous or semi-continuous motion along corneal trackpatterns, so as to penetrate through the cornea to a retinal target.

FIGS. 58A-C illustrate an embodiment for tracking retinal motion byaltering beam path using a moveable collimator exit plate.

FIGS. 59A-D illustrate an eye-guide device for use in a eye stabilizingsystem having aspects of the invention, the guide having a widow ortransparent portion permitting retinal imaging during treatment.

FIGS. 60A-E illustrate an alternative eye-guide device having a widow ortransparent portion; and having a support arm structure comprising aplurality of joints.

DETAILED DESCRIPTION

The following disclosure is related to the subject matter with is foundin the priority applications, in particular U.S. application No.61/093,092 filed Aug. 29, 2008; No. 61/076,128 filed Jun. 26, 2008; Ser.No. 12/103,534 filed Apr. 15, 2008; Ser. No. 12/100,398 filed Apr. 9,2008; Ser. No. 12/027,069 filed Feb. 1, 2008; each of which isincorporated by reference, to which the reader is directed for furtherdescription and examples which are relevant to the disclosure herein. Inparticular, these applications describe devices and methods of ocularradiotherapy, methods of planning treatments, and eye alignment andstabilization devices and methods having aspects of the invention.

Embodiments for Highly-Collimated External Beam Therapy

As described in detail below, embodiments of methods and devices of theinvention include a number of aspects which may be usefully employed incombination or separately, and which may be advantageously used to treata range of disease conditions, both of the eye and other regions of thebody. The examples described in particular detail focus on treatment ofconditions of the eye, and in particular, the retina of the eye, such asthe treatment of wet age-related macular degeneration (AMD).

It should be noted, however, that the methods and devices of theinvention are not limited to such use, and the priority applicationsincorporated by reference describe a broad range of applications (seefor example Ser. No. 11/956,295 filed Dec. 13, 2007). Examples includeradiotherapy on tissue in the anterior chamber following glaucomasurgery, such as trabeculoplasty, trabeculotomy, canaloplasty, and laseriridotomy, to reduce the likelihood of postoperative complications; andin the treatment of drusen, and the like. In some embodiments, x-raytherapy is combined with invasive surgery such as a vitrectomy, cataractremoval, trabeculoplasty, trabeculectomy, laser photocoagulation, andother surgeries.

In addition, while the embodiments described in particular detail belowemploy treatment beams of orthovoltage X-rays, many aspects of theinvention may be usefully applied with other forms of externallydelivered electromagnetic radiation. Planned and directed radiotherapymay include gamma radiation, higher energy x-rays, ultraviolet, visible,infrared, microwave, and radiowave energies.

A principal embodiment having aspects of the invention includes anintegrated system optimized for treatment of ocular diseases such asAMD, providing stereotactic, low energy X-rays delivered externally astightly collimated beams, together with synchronous application ofreal-time ocular tracking and/or ocular stabilization and control. Inthe preferred embodiments, the treatment is delivered a multiple X-raybeams through selected sites of the pars plana to precisely overlap onthe macula over small, well-defined treatment regions, so as to minimizeor avoid dosage to critical non-target structures such as the ocularlens, optic disk and optic nerve. Additional aspects of the inventioninclude integration of patient-specific data in phantom modelsrepresenting the treated eye, and use of these models to plan treatmentand treatment beam parameters, to assess the effects of eye motion onactual absorbed radiation dosage, and to provide real-time confirmationand control of treatment dose distribution. Additional embodimentsinclude sub-systems and sub-methods which may be employed with varioustreatment and diagnostic modalities.

Comparison of Prior Art with Inventive Treatment Embodiments

A body of published literature describes the use of radiation treatmentof diseases of the eye, including malignancies as well as benigndiseases such as pterygia, AMD, glaucoma, and vascular malformation.These studies indicated that radiation has promise in the treatment ofsuch diseases, and in particular Age Related Macular Degeneration. Itshould be noted that in prior art radiation treatment of the eye for AMD(and for other diseases treated), the devices used in the trials werenot customized or developed to treat the eye and specifically the maculafor macular degeneration. In addition, during treatment, there waslimited, if any, verification of the orientation of the eye relative tothe pre-operative CT scan or verification of maintenance of eyeorientation during treatment.

An example of prior art radiation treatment for AMD is shown in FIG. 1(see also FIG. 11H and discussion in priority application Ser. No.12/100,398 filed Apr. 9, 2008, which is incorporated by reference). FIG.1 compares a prior art radiation beam 5 (see Marcus et. al.,Radiotherapy for recurrent choroidal neovascularization complicatingage-related macular degeneration; Br. J. Ophthalmology, 2004; 88 pps.,114-119, which is incorporated by reference), with a finely collimatedorthovoltage radiosurgery treatment beam 11 emitted by a radiotherapysystem 10 having aspects of the inventions herein, each treatment beamshown superimposed on a CT scan 20 of the anterior portion of a patientshead 22.

The prior art treatment beam 5 is representative of previous treatmentsusing external beam radiation to treat AMD, and is produced by a largelinear accelerators were used without localization or customizationspecifically for the eye, having an energy of about 6 MeV. The priortreatment beam path 6 has a very large field size (about 3 cm diameter)which covers the entire posterior pole of the retina and the optic nerve24 of the treated eye 26. Furthermore, although the prior art beam path6 has been angled to reduce radiation to the non-target eye 30, thecontralateral optic nerve 32 extends well within the beam path 6.

Due the penetrating nature of the MeV radiation and the beam width,among other things, prior art treatment beam 6 results in substantialirradiation of the non-targeted structures. Note that the 90-100%isodose volumes encompass the entire ipsiliateral retina, optic nerveand optic disk, while the contralateral optic nerve of the non-targeteye receives about 63% of the maximum dose. The dosage of the trialsdescribed in Marcus were: at 100% isodose about 2 Gy per fraction, andat 63% isodose, about 1.26 Gy per fraction (Marcus, D. M. et al.,External beam irradiation of subfoveal choroidal neovascularizationcomplicating age-related macular degeneration: one-year results of aprospective, double-masked, randomized clinical trial, Arch Ophthalmol,2001 119(2): p. 171-80, which is incorporated by reference).

Due to substantial irradiation of the non-targeted structures, the priorart treatment, the treatments performed in Marcus et. al. requiredfractionation of the dose over many days and with small fractions inorder to prevent damage to normal tissues. In addition, these prior artattempt at applying radiation to the macula did not consider eyemovements or eye position. This requires administering the doses under afractionation protocol with up to 7 treatments of the lesion. Suchfractionation and minimalist dosing and planning schemes likely lead tothe lack of efficacy in those studies. The study generally showed thatat 1-year follow-up, the particular low-dose external beam irradiationused, at 14 Gy in 7 fractions of 2 Gy each, is neither beneficial norharmful for subfoveal CNV complicating ARMD.

In contrast, the beam path 12 of a finely collimated orthovoltage X-raybeam 10 is also depicted. In the particular treatment embodiment shown,a micro-collimated beam 10 of about 100 keV is emitted to enter thesclera of eye 30 in a very small beam spot at the pars plana region 34,the beam path 12 having an orientation configured to effectively avoidcornea 35, lens 36 and optic nerve 32 of target eye 30. Beam 10 has beenexperimentally and theoretically verified to deliver a dose of about 18Gy to the sclera, penetrating there-from to the retina to deliver atherapeutic dose of about 8 Gy to the macular region 38. Thereafter, theradiation is scattered by the bone behind the eye to about 1-2 Gy atpoint 40 in the brain and quickly attenuates to about 0.5 Gy at point 42in the brain tissue and the bone of the skull 22.

As is discussed in detail elsewhere in this application, embodiments ofradiosurgery treatment beams having aspects of the inventions employorthovoltage X-ray beams of a carefully selected maximum energy andspectral characteristics, a favorable ratio of scleral surface dose todelivered macular dosage may be provided (in this example, about2.25:1). In addition, modest maximum photon energy provides rapidattenuation of the treatment beam beyond the target region, minimizingdosage to non-targeted structures. When multiple beams havingstereotactically aligned target regions, these advantages be increased.In the example shown in FIG. 1, three such beams emitted along paths atdifferent angles on the eye (different surface entry points) can providea dosage summation on the macula of 24 Gy, with only 18 Gy to each entrypoints on the sclera.

Another significant limitation of the treatments in prior art externalbeam trials, there was no accounting for eye movement and positionduring the treatment. The CT scan 20 in FIG. 1 represents an ideal caseand it was assumed that the eye position during the treatment time(30-60 s) was similar to the CT scan and constant. However, the eyemovement and the center of rotation vary from patient to patient, and itis difficult to know the exact dose applied to the macula.

FIG. 2 similarly depicts the target region of the posterior eye 50receiving a prior art proton treatment beam 52 (Adams, J. et. al;Medical Dosimetry 24(4) 233-238, which is incorporated by reference). Inthis study, the proton beam is centered on macula 54, although the 90%isodose line encompasses both the macular and the entire optic nerve 56.In addition, eye location and movement were not controlled in thisstudy. The authors of this study reported significant complications,likely due to the very broad coverage of the retina with 20-24 Gy ofproton beam radiation in 12 Gy fractions. Such complications likelynegated any benefit of the therapy. The x-ray delivery methods havingaspects of the invention described herein allow for delivery only to themacula where the disease exists while limiting or avoiding delivery ofx-rays to other regions that are not diseased.

As is discussed in detail elsewhere in this application, embodimentsemploy a number of methods for incorporating both control andverification of eye position and movement during radiation treatment.Other embodiments incorporate patient-specific data such as fundusimages, OCT and A-scans, in phantom models used to plan and controltreatment and used to assess actual administered dosage distribution ona real-time basis.

It should be noted with emphasis that device and methods having aspectsof the invention have utility and advantages over the prior art intreatments other than those described in particular detail below. Forexample, higher energy radiation (greater than 500 keV) may also beadvantageously employed using methods of the invention for treatment oflesions of the eye and other parts of the body. Methods of controllingand tracking eye motion described herein may be advantageously employedwith other treatment and diagnostic modalities. Methods of producing andusing phantom models incorporating patient-specific data may be used fortreatments for diseases other than AMD, and for treatments other than tothe eye.

Radiotherapy Overview

FIG. 3 shows a schematic overview of an embodiment of a treatmentplanning system and method 800 having aspects of the invention, which isdepicted as a global interconnect encompassing four subsystems. Thetreatment planning system (TPS) 800 also provides the interface betweenthe physical world of the eye, the physical components of the system,and a virtual computer environment which interacts with the physicianand treatment team and contains the specific patient and diseaseinformation. The treatment planning system 800 directs the foursubsystems in treatment of the region and/or disease as directed by thephysician. The four subsystems in general terms include an X-raysubsystem 700 (producing treatment radiation), a coupling subsystem 500(aligning to and/or stabilizing the tissue being treated), anelectromotive subsystem 600 (positioning the x-ray subsystem), and animaging subsystem 400 (capturing information from the coupling system,the x-ray subsystem and the patient). In some embodiments, maximum beamenergy X-ray subsystem 700 is set by the treatment planning system 800in order to create doses and plans for specific diseases. The couplingsystem 500 and the imaging system 400 function to link the physicalworld (patient and treatment device) and the virtual world (e.g.,computer model of treatment plan incorporating patient-specific data.These subsystems or modules interact to provide an integrated treatmentto the eye of a patient.

The treatment plan is developed based on a combination of biometricmodalities including an imaging subsystem 400 that can include, forexample, fundus photography, or optical coherence tomography, CT scans,MRI scans, and/or ultrasound modalities. The information from thesemodalities are integrated into a computer-generated virtual model of theeye which includes the patient's individual anatomic parameters(biometry) as well as the individual's specific disease burden. Any orall of these modalities can be utilized by the system in real time orintegrated into the system prior to treatment. The treatment plan isoutput, for example, on the interface display 130 module of theradiotherapy system 10. The physician can then use the virtual model inthe treatment plan to direct the radiation therapy to the disease usingthe radiotherapy system 10.

As used herein, “eye model” or “model of the eye” refers to anyrepresentation of an eye based on data, such as, without limitation, ananteroposterior dimension, a lateral dimension, a translimbal distance,the limbal-limbal distance, the distance from the cornea to the lens,the distance from the cornea to the retina, a viscosity of certain eyestructures, a thickness of a sclera, a thickness of a cornea, athickness of a lens, the position of the optic nerve relative to thetreatment axis, the visual axis, the macula, the fovea, a neovascularmembrane, a curvature of a cornea or a retina, a curvature of a scleralregion, and/or an optic nerve dimension. Such data can be acquiredthrough, for example, imaging techniques, such as ultrasound, scanninglaser ophthalmoscopy, optical coherence tomography, other opticalimaging, imaging with a phosphor, imaging in combination with a laserpointer for scale, CT scan with or without contrast, and/or T2, T1, orfunctional magnetic resonance imaging with or without contrast. Suchdata can also be acquired through keratometry, refractive measurements,retinal nerve-fiber layer measurements, corneal topography, directcaliper measurement, etc. The data used to produce an eye model may beprocessed and/or displayed using a computer. As used herein, the term“modeling” includes, without limitation, creating a model.

The eye model is a virtual model which couples the anatomy of the eyewith the coordinate system of the radiotherapy device. The eye model canbe based on the geometry of the ocular structures and can be derivedwith parametric data and mathematical formulas to generate the model.Alternatively, the ocular geometries are derived from cross-sectionalimaging, such as from CT scans or MRIs. With the treatment axis definedand the ocular anatomy defined, the coupling device can contact theocular surface and link to the radiotherapy device via the eye model.The radiotherapy device may then be positioned based upon the eye model.

FIG. 4, views A-C, show a schematic overview of the relation between thetreatment planning system and its eye model with various components ofradiotherapy system 10 in the treatment of eye 30. Within the virtualworld, the treatment planning system creates a computer-generatedvirtual model of the patient's eye 505 based on physical and biometricmeasurements taken by a health practitioner or the imaging system 400itself. The computer model 505 in the virtual world further has theability to simulate the projection 510 of an x-ray beam 520 from aradiation system 524 through an anterior region of the eye, which caninclude a traversal or intersecting zone 515, to the structure 514 to betreated based on different angles of entry into the eye. The model canalso identify and include important eye structures, such as the opticnerve 512, to consider during the treatment planning process. Thevirtual world also contains the physician interface to control thedevice 524 and interface the device with respect to the physical world,or that of the actual physically targeted structure. After integratingthe inputs from the physician and modeling the beam angles and desireddirection to direct the therapy, the virtual world outputs theinformation to the electromotive subsystem to move the x-ray device tothe appropriate position in three-dimensional space. The couplingsubsystem 500 (in the physical world) can include a mechanism todetermine the angle of incidence of the x-ray beam with respect to thesurface of the eye using one or more laser or angle detectors, asdiscussed above.

In some embodiments, the coupling system 500 contains a camera 518 whichcan image a spot (real, reflected, fiducial, or projected fiducial) 516on or in an eye; the camera can also visualize structures such as thepupil, cornea, sclera, limbus, iris, fundus, optic nerve, macula, or alesion to be treated. Information from the camera is then preferablytransferred to the virtual eye model 522 and again to the motion andradiotherapy system 524. In certain embodiments, the coupling system 500is a physical connection with the eye. In some embodiments, the couplingsystem 500 is not a physical link but is a communication link between alens on the eye and a detection system. For example, a lens can be acommunication beacon to relay eye position to the system 500. In someembodiments, the lens can contain markers that are imaged by the imagingcamera 518, through which the next stage in the therapy can bedetermined. In some embodiments, a combination of these techniques isused.

FIG. 5 depicts the relation of the treatment planning system 800 toother system components. Treatment planning system 800 forms the focusof an exemplary method of treatment using radiosurgery system 10. Incertain embodiments, the imaging module 400 of the system 10 includes aneye registration and imaging system 810. In certain embodiments, theeye-tracking system is configured to track patient movement, such as eyemovement, for use by the treatment planning system 800. The eye-trackingsystem 810 can calculate a three-dimensional image of the patient's eyevia physician inputs, and can include real-time tracking of movement ofthe patient's eye. The eye-tracking system obtains data for determiningradiotherapy treatment planning for a number of medical conditionsrelating to the eye, as described herein. For example, the eye-trackingsystem may create an image of the posterior region of the patient's eyeusing the data it obtains.

The treatment planning system 800 may utilize, or be coupled to, imagingsystems such as, for example, optical coherence tomography systems(OCT), ultrasound imaging systems, CT scans, MRI, PET, slit lampsmicroscopy systems, direct visualization, analogue or digitalphotographs (collectively referred to as Biometry Measurements 820). Insome embodiments, these systems are integrated into real-time feedbacksystems with the radiotherapy device such that second be second systemupdates of eye position and status can take place. Although relativelysophisticated, the system 800 may be limited to the ophthalmic regionand therefore takes advantage of specific imaging equipment onlyavailable for the eye. In some embodiments, the treatment planningsystem incorporates the soft tissue and bony structures of the head of apatient in addition to treated eye 30.

In some embodiments, the treatment planning system incorporates physicalmodeling techniques such as Monte Carlo (MC) simulation into thetreatment plan so that the real time x-ray doses can be delivered to theocular structures. In these embodiments, the inputs to the treatmentplanning system 800 are integrated with Monte Carlo simulation of theplanned treatment plan and the effects of the plan, both therapeutic andpotentially toxic, can be simulated in real time. In some embodiments,geometric ray tracing models are used with estimates based on priorMonte Carlo simulation. Ray tracing models with prior Monte Carlosupport rapid and real time simulation of dosimetry.

As depicted in FIG. 5, biometry measurements 820 and user controls 875such as anatomic structure and radiation dose may entered into thetreatment planning system 800. Other inputs include information from aneye registration and imaging system 810. The output from the treatmentplanning system 800 consists of commands sent to the x-ray source andelectromotive subsystem to move and position the source as well as todirect the on and off times (dose control) of the x-ray source 830. Insome embodiments, maximum beam energy is set by the treatment planningsystem in order to create doses and plans for specific diseases. After adose 840 is delivered, the treatment planning system 800 then signalsx-ray source movement to deliver an additional dose 840. This cycle caniterate several times until the treatment is completed.

FIG. 6 depicts an exemplary clinical flow method involving theradiotherapy device 10. An imaging modality and physical exam 3500 areused to create an eye model 3510, through which a 3D coordinate map isgenerated. The dose for a specific disease is chosen as is the maximumbeam energy based on the region to be treated as well as the region tobe avoided. These variables can be determined by treatment software aswell as physician input related to the disease as well the depth of thediseased tissue. The patient is then positioned, and the optionalcontacting device is placed against or close to the eye of the patient3520. The patient and radiotherapy device are aligned with the guide3530, and the treatment of a dose of radiation is applied 3540.Optionally, an imaging system is included in the unit and optionally aneye tracking system is included in the unit. Furthermore, a gatingsystem may also be incorporated into the system in which the device isturned off with a pre-determined amount of eye movement.

FIG. 7 depicts a cross-sectional view of an eye 30, shown in associationwith an embodiment of a radiotherapy system 300 having aspects of theinvention. In the example shown in FIG. 7, target 318 is centeredapproximately the fovea 344, and collimated orthovoltage X-ray beam 311at entry to the sclera may have a effective beam with of W_(e) (e.g., asdefined by a boundary at the 90% isodose). The beam 311 spreads at itpropagates through the eye, to have an effective beam width of W_(t),which covers an area surrounding the target constituting the treatmentregion, in this case corresponding to the macula.

In the example shown, for beam axis 311, a rotational angle Φ may beselected to define a propagation path for the beam which avoidsvulnerable structures such as the optic nerve 350. Note that thetreatment axis 19 may be different from geometric axis 18, selectedhaving a known position and orientation with respect to axis 18. Forexample, axis 19 may have a lateral offset from geometric reference axis18, and the rotational angle Φ may be selected to assure a desiredminimum corneal clearance for beam entry.

The positioning device 310 may conveniently have actuators providing forseveral degrees of freedom of motion for treatment device 312, such a 5DOF device providing x-y-z adjustment relative to the patient's eye, androtation for the angles Φ (angle with respect to treatment axis 18) andθ (angle of rotation around treatment axis 18) as is further describedbelow. See, for example the constrained positioning system for an X-raysource and collimator, as described and shown with respect to FIGS.12E-F of co-invented/owned U.S. patent application Ser. No. 12/100,398,entitled “Orthovoltage Radiosurgery” filed Apr. 9, 2008 by Gertner etal., which is incorporated by reference. Further exemplary embodimentsof radiation source positioning systems are described with respect toFIGS. 33-38 herein.

Radiotherapy system 300 may include an eye positioning and/orstabilizing device 110, such as is described further in FIGS. 39-49herein. See also in particular the eye positioning, aligning and/orstabilizing devices and methods described in co-invented/owned U.S.patent application No. 61/076,128 filed Jun. 26, 2008; Ser. No.12/103,534 filed Apr. 15, 2008; and Ser. Nos. 12/027,083, 12/027,094 and12/027,069, each filed Feb. 1, 2008; each of which is incorporated byreference.

Without departing from the spirit of the invention, one of ordinaryskill in the art will appreciate that for a specialized device optimizedfor a particular range of treatments, fewer degrees of freedom may beprovided, as, for example, when certain of the parameters described mayreasonably be fixed. Note in this regard that an eye positioning and/orstabilizing device 110, such as shown if FIGS. 39-40 herein, may includeactuators (or employ manual patient movement) sufficient to change theposition and orientation of the treated eye 30, so as to substitute fordegrees of freedom of the positioning device 310 with respect to thetreatment device 312. Thus, the patient and/or eye may be moved in oneor more parameter with respect to device 312, until it is determinedthat the treatment path 311 is correctly aimed at target 318 (which maybe confirmed by the alignment system).

In some embodiments, one or more additional imaging camera systems maybe included. In the example shown in FIG. 7, camera 322 is configured tobe positioned by positioning device 310, and aimed so as to obtain animage of the area of intersection of therapeutic beam 311 with anexposed body surface, such as an exposed area of the scleral surface ofthe eye. Additionally, a reference light beam may be provided toilluminate and/or mark the of intersection area. For example, device 312may incorporate a laser pointer beacon along a path coincident withtherapeutic beam 311 (e.g., directed by a co-aligned mirror), so as toindicate the intersection of beam 311 on a surface of the eye (e.g., forvisual or automated confirmation of the alignment of beam 311, or thelike). Alternatively, a reference light beam may be provided which isnot aimed along a path coincident with therapeutic beam 311, forexample, configured to be aimed by positioning device 310 on a pathintersecting the surface at area (see FIG. 2C and related description ofco-owned U.S. application Ser. No. 11/873,386 filed Oct. 16, 2007, whichis incorporated by reference).

Further description of particular aspects of system 10 may be foundbelow and in the priority applications, in particular Ser. No.12/103,534 filed Apr. 15, 2008; Ser. No. 12/027,069 filed Feb. 1, 2008;and Ser. No. 12/100,398 filed Apr. 9, 2008; each of which isincorporated by reference.

Orthovoltage Radiation Characteristics

Medical X-rays are typically produced by accelerating electrons in orderto collide with a metal target, the X-rays being emitted as theelectrons interact with the target material. Higher energy X-rays(typically greater than about 1 MV) may be produced by electronsaccelerated by linear particle accelerators (LINAC). Lower energy X-rays(typically less than about 600 kV) are generally produced by electronsaccelerated from cathode to anode in an X-ray tube.

In the X-ray tube, the electrons suddenly decelerate upon colliding withan metal anode target. The X-ray spectrum produced is characterized by abroad “bremsstrahlung” or braking radiation spectral curve resultingfrom the interaction of the accelerated electrons with the target anodematerial. This process induces X-ray emission over a smoothly varyingrange of photon energy levels (wavelengths), corresponding to thestatistical variation in the electron energy loss during deflection byatomic nuclei, the spectrum reaching a maximum photon energycorresponding to the magnitude of anode-to-cathode tube potential field.There are also superimposed distinct narrow spectral peaks(characteristic lines) corresponding to discrete energy leveltransitions within the atoms of the anode material (e.g., tungsten,copper or the like) as atomic electrons interact with thefield-accelerated electrons.

Within the x-ray regime of electromagnetic radiation, low energy x-rayscan be referred to as orthovoltage. In some usages, the X-ray regime ismore finely subdivided with respect to maximum spectrum photon energy soas to correspond to types of medical and industrial applications (suchas diagnostic X-rays 20-50 kV; superficial X-rays 50-200 kV;orthovoltage X-rays 200-500 kV; super-voltage X-rays 500-1000 kV; andmegavoltage X-rays 1 to 25 MV).

However, for the disclosure herein, the term “orthovoltage X-rays”includes X-ray radiation having a spectrum with maximum photon energiesfrom about 20 kV to about 500 kV. This includes radiation which incertain medical usage may be referred to as “superficial” or“diagnostic” in reference to a relatively reduced tissue penetration.Methods of selection of an X-ray spectrum, including maximum photonenergy and filtration, for employment in a particular radiotherapytreatment plan are described and shown with respect to variousalternative embodiments having aspects of the invention.

FIG. 8 depicts an exemplary set of orthovoltage X-ray spectra showing atrend of characteristic photon energy distribution with increasingsource tube voltage, for a number of examples of tube potential. Theterm “kVp” refers to the maximum (peak) voltage of the x-ray powersupply to the X-ray tube. When x-rays are generated by electronsaccelerated in the high voltage electrical potential field of typicalX-ray tube, a spectrum of x-ray of various photon energies is obtained.This spectrum is characterized by a broad bremsstrahlung spectral curvefor each x-ray source kVp level. For the higher tube kVp levels (e.g.,about 80 kVp and above), there is superimposed on the bremsstrahlungspectrum a series of characteristic lines corresponding to atoms of theanode material (e.g., tungsten).

The maximum voltage (tube kVp) is typically identical to maximum X-rayphoton energy of the emitted spectrum, showing linear variation over theplotted range of tube potentials. For example, the 80 kVp spectra inFIG. 8 has a maximum of 80 keV with a leftward tail of lower energyradiation. Similarly, the 60 kVp spectrum has a maximum of 60 keV with asimilar leftward tail. It may be also seen that the photon energycorresponding to the peak of the photon flux curve (peak flux energy)increases with increasing tube potential, although non-linearly. In thisfiltered example, the peak flux energy changes from about 28 keV toabout 35 keV over the potential range of 40 to 80 kVp.

All spectra in FIG. 8 have been filtered through 3 mm of aluminum(extrinsic filtration) in addition to penetrating the X-ray tubestructure at the exit window (intrinsic filtration, e.g., 0.8 mmberyllium). Filtering re-shapes the spectral curve. Each energy ofphoton attenuates through matter at a different rate, whether the matteris patient tissue or an extrinsic filter material such as aluminum. Forinstance, a mono-energetic flux of 10 kV x-rays incident on a block ofaluminum will be attenuated by a factor of 2 (to half intensity) afterabout 0.1 mm, while a mono-energetic flux of 100 kV photons will be ableto penetrate almost 22 mm before losing half their intensity. Thus lowerenergy photons (longer wavelengths) are filtered or absorbed to agreater degree than higher energy photons (shorter wavelengths).Absorption by the filter material tends to eliminate variation in thespectra of the different tube kVp levels over the low photon energyrange, with each spectrum in this example substantially absorbed atphoton energies below about 20 keV.

Filtering of the raw spectra is useful to customize the x-ray energy forthe application at hand where the lower energy photons, if not filtered,would be absorbed by superficial structures near the body surface (e.g.,the sclera of the eye), while higher energy photons can propagate todeeper tissue. In an example of radiotherapy applied to a retinallesion, to the extent that it is desired that x-ray energy reach thestructures of the retina with minimal energy absorption by the anteriorstructures of the eye, filtering of the raw spectra is advantageous;with filtering, the resulting spectrum contains a greater amount of highenergy photons than low energy photons. As described, for some diseaseprocesses, it is desirable to have a predominance of low energy x-rayreach the anterior structures of the eye in which case the lowervoltages will be used with correspondingly lower keV peaks. Adjustmentof the power on the power supply will result in a decrease in the peakvoltage of x-rays, limiting the amount of higher energy photons. In someembodiments, it may be desirable that a non-uniform filter be used. Forexample, the filter may have varying thicknesses across it toaccommodate varying differences in the X-ray spectra in one treatmentregion.

FIG. 9 depicts an set of 80 kVp X-ray spectra showing a trend of photonenergy distribution with increasing thickness of filter material(aluminum plate). It may be seen that without external filters, thespectrum emitted by a typical X-ray tube includes a large flux at lowphoton energies. The effect of increasing filter thickness (curves for 1mm, 2 mm and 3 mm of Al plate) may be seen to substantially reduce thetotal area under each curve, reducing the total X-ray flux.

However, it is also readily apparent that the reduction in X-ray flux(moving towards increased filter thickness) is more dramatic at the lowenergy portion of the spectrum at the right of the plot (leastpenetrating photons), and has little effect on the flux of the higherenergy photons at the left of the plot (most penetrating photons). Thiseffect can be seen indicated by the shift of peak flux energy to theleft with increasing filter thickness, from about 30 keV to about 37 keVover that thickness range of 1 to 3 mm aluminum. As a consequence, wherethe filtered X-ray beam is to be directed into tissue, the selection ofthe filter thickness alters the proportion of photons which are absorbednear the tissue surface relative to the portion absorbed at any selectedtarget depth, as further describe herein. Embodiments having aspect ofthe invention employ this effect to obtain highly advantageous treatmentbeam properties.

FIGS. 10 and 11 demonstrate the effect of filter selection on the ratioof radiation dosage absorbed at tissue surface to that absorbed at aselected tissue depth, as a function of filter thickness and X-ray tubepotential (maximum photon energy). The data shown has been demonstratedby inventors herein both through simulations (“Monte Carlo” simulationusing MCNP Radiation Transport Code developed by Los Alamos NationalLaboratory), and by radiometric experiments using water-equivalentphantom material, which may be referred to herein as “solid water”.Several generally similar water-equivalent phantom formulations arecommercially available from different sources; the one used in the datapresented was Solid Water® by Gammex Inc. of Middleton, Wis.

FIG. 10 is a plot showing the depth propagation/absorbs ion curve for anexemplary treatment beam penetrating simulated tissue (solid water). Thebeam is emitted at 100 kVp, filtered by a 0.8 mm Be tube window and 0.75mm Al external filter. The plot is the dose fraction (vertical axis)reaching a given depth or thickness of solid water (horizontal axis),which may be referred to as “path length”. In an example relevant tocertain ocular radiotherapy embodiments, a tissue path length of about19 mm is within the typical anatomical range for the retinal depth for abeam entering near the pars plana of the eye.

It may be seen that for this path length, the fractional depth dose isabout 0.35, and thus for these beam parameters, about ⅓ of the X-rayflux reaches this tissue depth, the balance of about ⅔ of the fluxhaving been absorbed within the volume extending from 0 to 19 mm. Thismay be referred to herein as dose surface-to-depth ratio, which is theinverse of fractional depth dose, although both expressions may be seento be indicative of the same physical effect.

FIG. 11 is a plot showing the effect of a range of X-ray tube potentials(maximum photon energy) and the effect of two different filterthicknesses (1 mm and 3 mm Al) on the depth-dose ratio in simulatedtissue, measured at a typical retinal depth or path length of about 20mm. While differing soft tissue composition and anatomical dimensionswill alter data in detail, the trends shown are characteristic andinstructive of the principles employed in method and device embodimentsherein.

It will be seen in FIG. 11 that for both filter thicknesses, there is atrend towards a lower ratio of surface or entrance dose to depth dose asthe tube potential increases, which is implied also by the data of FIG.8, in that for a given filter thickness, increased tube kVp results aflux dominated by more penetrating photons. It will also be seen in FIG.11 that the effect of increasing filter thickness is to reduce thesurface-to-depth ratio over the entire range of tube potentials. Thetrend for both filter thicknesses is that the slope of each curvedecreases as the tube potential is increased, further increments of tubepotential resulting in smaller decreases in surface-to-depth ratio.

FIG. 12 depicts an exemplary sequence of spectra corresponding to thepropagation of a radiotherapy beam through system filters and simulatedpatient tissue anatomy. This example is configured as an oculartreatment via a narrowly collimated beam entering through the scleranear the limbus and penetrating through the macula and orbital tissueand bone. The beam parameters include a tube potential of 100 kVp with a0.8 mm Be tube window and 0.75 mm Al filter. An energy spectra analysiswas performed based on an “Monte Carlo” simulation (MCNP RadiationTransport Code developed by Los Alamos National Laboratory) of theeffects of matter on the propagation and absorption of a typical X-raybeam emitted at a potential of 100 kVp (e.g., Comet MXR160HP/11 tube).Monte Carlo modeling begins with a defined input spectrum, anddetermines to dose at any arbitrary point of propagation by statisticalmodeling, and thus may be used to determine the dose received by variouslevels within tissue.

The modeled beam begins with a 100 kVp bremsstrahlung spectrum at thesurface of the tube anode. The “scleral spectrum” is the spectrum afterfiltration through the beryllium window and aluminum filtration,propagating through air to the tissue surface. The resulting averagebeam energy is determined to be about 47 keV at the scleral surface(half the photon flux higher, half lower). The “macular spectrum” isfurther “hardened” by the passage through 19 mm of tissue and theaverage energy is determined to be about 52 keV at the macula. Thesespectra were verified with bench-top measurements using a spectrometer;however, the Monte Carlo simulations are more precise. A furtherfiltered or hardened “brain” spectrum is shown representing the fluxpassing from the macula through orbital tissue and bone. Note from thesurface areas under the curves that the flux passing beyond the maculartreatment target is a small fraction of the input to the sclera.

Note that an X-ray tube potential voltage employed in orthovoltageradiotherapy systems having aspects of the invention may be greater orless than the ranges of kVp shown in FIG. 8 through FIG. 12, withoutdeparting from the spirit of the invention. A source voltage and/orfilter properties may be selected according to embodiments describedherein to obtain particular therapy beam properties (e.g., depending ondepth of target, propagation tissue path, desired dose distribution andthe like).

Monte Carlo Simulation and Validation of Ocular Treatment

As may be seen from FIG. 12, radiation modeling may be employed topredict the effect of a particular radiation beam on structures withinthe body. FIGS. 13 to 17 illustrate the application of these techniques,combined with anatomical models of treatment regions to determine themost advantageous treatment plan for a particular therapeuticapplication. In the examples shown, the treatment plan is directed toradiation applied to a lesion on or adjacent the retina, near thecentral axis of the eye. In general, FIGS. 13 and 14 illustrate asub-method embodiment of treatment planning including selecting beampaths in the Φ angular direction (with respect to an Y-Z plane); andFIGS. 15-17 illustrate a sub-method embodiment of treatment planningincluding selecting beam paths in the azimuth θ angular direction (withrespect to an X-Y plane). Both sub-methods may be advantageously carriedout using computational simulations of radiation effects, by physicalmeasurements, or by a combination of these.

As described with respect to FIGS. 8-12, Monte Carlo (MC) simulationsare used to model x-ray absorption, scatter, and dosing to structuresimpinged on by x-rays. An example of a tool useful for this type ofanalysis is the MCNP Radiation Transport Code developed by Los AlamosNational Laboratory (see D B Pelowitz; MCNPX User's Manual Version2.5.0, LA-CP-05-0369; Los Alamos National Laboratory, Los Alamos, N.Mex., 2005, which is incorporated by reference herein). Monte Carlomethods are widely used computational algorithms for simulating thebehavior of various physical and mathematical systems, and for othercomputations. They are distinguished from other simulation methods (suchas finite element modeling) by being stochastic, that is,non-deterministic in some manner. Computational radiation simulations,such as Monte Carlo analysis and the like, are included in embodimentsof treatment planning systems having aspects of the invention, and maybe used to assist in treatment planning where radiation is involved.

Monte Carlo simulation can also be used to predict and dictate thefeasibility and other elements of the radiotherapy system 10 (e.g.,optimization of the collimator and treatment planning schemes); forexample, the collimation designs, the energy levels, and the filteringregimes, can be predicted using Monte Carlo simulation. The results ofMonte Carlo simulation have been experimentally verified and furtherimproved, based on initial MC simulation. In some embodiments ofradiotherapy where the anatomy, beam energies, and treatment volume aresimilar, the Monte Carlo simulations can be run once and then the pathvariables altered (e.g., through ray tracing or other geometricmethodology) without need to repeat Monte Carlo simulation.

In some embodiments, MC simulation is integrated into the treatmentplanning systems and in other embodiments, MC simulation providescertain algorithms used by the treatment planning system 800 (see FIGS.3-6). MC simulation may be in a treatment planning system to createboundaries of treatment. For example, MC simulation can predict thepenumbra of an x-ray beam. The penumbra of the x-ray beam is used invirtual world models (see FIGS. 20-24) of to direct the x-ray beam andset boundary limits for the x-ray beam with respect to the lens, opticnerve, etc.

Some embodiments of X-ray treatment system having aspects of theinvention are optimized for treatment of age-related maculardegeneration (AMD). In alternative embodiments, the x-ray system 10 isused to treat post-surgical scarring in procedures such as laserphotocoagulation and laser trabeculotomy or laser trabeculectomy. Insome embodiments, the x-ray system is used to treat pterygia, oculartumors or premalignant lesions such as hemangiomas and nevi.Importantly, the x-ray treatment system allows for selective irradiationof some regions and not others. In some embodiments, radiation isfractionated over a period of days, months, or weeks to allow for repairof tissues other than those which are pathologic or to be otherwisetreated. The description of embodiments herein demonstrate thatorthovoltage radiation can be delivered to the retina to treat AMD in aclinically relevant time period from a clinically relevant distance; anddescribe the parameters of such a treatment system.

FIG. 13 illustrates a representative geometric model of the eye used formodeling purposes, showing representative radiation beam angles withrespect to an anterior surface and geometric axis of the eye. FIG. 14depicts results of Monte Carlo simulations performed to analyze theeffect of various treatment regimes on the various structures of theeye.

The model of FIG. 13 illustrates a virtual or phantom model of a humaneye and adjacent structures, such as may be digitally defined usingconventional software tools, displays and input/output devices, and thelike. A virtual model may include multiple components, which includedifferent representations of the same anatomical structures. Soft tissueand hard tissue (e.g., bone 2065) was incorporated into the model. Axis2082 is the geometric axis of the eye, which is further described hereinwith respect to alignment systems for a radiotherapy device 10.

Within the model are defined representative radiation beam paths, inthis example indicated as beam angles 2100, 2110, 2120, 2130, 2140respectively, the beam paths being defined with respect to the axis 2082to simulate therapy to the macular region to treat AMD. In thissimulation, each beam enters the eye at a different polar angle Φ fromthe geometric central axis 2082. In this example, the geometric axis isassumed to be the treatment axis of the eye, although as describedherein, the treatment axis may have a different position andorientation, relative to the geometric axis. Each of beams 2011-2140follows a different path through the eye and affects structures, suchas, for example, the macula 2094, optic nerve 2085, lens 2075, sclera2076 (adjacent but removed from the pars plana), cornea 2080, and fovea2092 differently depending on the path through the eye. This modelingmay be used to determine the angle of radiation delivery of theradiotherapy device and may be incorporated into a treatment planningalgorithm. For example, in FIG. 13, beam 2120 enters the eye directlythrough the eye's geometric axis; whereas beam 2100 enters through thepars plana.

In the study, a series of x-ray energies were modeled using an exemplaryrange of X-ray tube potentials from about 40 kVp to about 80 kVp. Acollimation structure was included in the model, configured to produce anarrow, near-parallel beam, as was a series of different filters (about1 mm to about 3 mm thickness aluminum). The combination of angle ofentry of the beam, photon energy of the beam, and filtration of the beamall factor into the relative amounts of energy deposition to the variousstructures.

FIG. 14 is a bar graph showing representative results from the MonteCarlo study using the model of FIG. 13, for an exemplary study case ofbeams emitted at an 80 kVp tube potential with the spectrum modified bya filter of 1 mm aluminum. The graph shows scatter doses to ophthalmicregions other than the retina and pars plana, and comparing them to themacula dose. In this plot, the dose is the radiation absorbed by thetissues indicated, measured in Gray (Gy), for a treatment which isscaled to deliver a 25 Gy dose absorbed by the macula target.

As can be seen in the logarithmic figure, the dose to the lens 2400(beams 2100 and 2140) and optic nerve 2410 (beam 2140 alone), the twomost sensitive structures in the eye, are at least an order of magnitudelower than the dose delivered to the macular region 2450 of the retina.Other beam angles result in distinctly higher doses to these structures.Therefore, a 25 Gy dose of radiation can be delivered to a region of theretina through the pars plana region of the eye with at least an orderof magnitude less radiation reaching other structures of the eye such asthe lens, the sclera, the choroids, retinal regions remote from themacula, and so forth. Beam 2140 is generally representative of the beamorientations (as exemplified in the Y-Z plane of the eye) which areemployed in preferred embodiments of methods and devices described indetail herein (see FIGS. 15-17).

These simulations may be advantageously employed in the design of X-raytreatment systems and subsystems having aspects of the inventions. Thesesimulations can also be integrated into the treatment planning system800 as a component of the plan so that doses to therapeutic targets mayrelative to doses to critical structures may be predicted. In addition,as further described herein, the data from such radiation simulationsmay be adjusted to specific patient anatomical imagery and measurements,and may be used to determine actual treatment results, including theeffects of unintended patient movement and the like (see discussion withrespect to FIG. 19, among other places). For example, the planningsystem, which incorporates the unique anatomy of each patient, cansimulate the amount of radiation delivered to each structure dependenton the angle and position of delivery through the sclera. Depending onthe angle, beam size, and beam energy, the radiation delivered to theocular structures will vary and alternative direction can be chosen ifthe x-ray dose is too high to the structures such as the lens and theoptic nerve.

As shown in FIGS. 13 and 14, the lowest and highest angled beams 2100and 2140 avoid significant absorbed dosage to the lens by adopting apolar angle Φ sufficient to provide clearance from the limbus of theeye, thus avoiding irradiation of the cornea or lens. For example, for abeam spot diameter of a few millimeters with entry point in the parsplana region, a polar angle Φ of about 30 degrees from the geometricaxis may be selected, and this is the constant polar angle for each ofthe beams defined in FIG. 15. Note that further increases in polar anglemay present inconvenience or discomfort with respect to the range ofeyelid retraction, or by interference with the beam by tissues adjacentthe eye. For such a fixed polar angle of about 30°, the collimated beammight still result in some radiation scatter from eye tissue producing acertain dose gradient across the lens margin. However, it may be seenfrom FIG. 14 that this scatter (2400) is at least 2 orders of magnitudeless than the macular dose. Furthermore, in a multiple beam stereotactictreatment plan, by entering the eye from more than one azimuth angle todeliver the selected total macula dose, any such scatter gradient willfurther “smeared out” around the lens margin by the orientations ofdifferent beams. Thus the scatter dose region will shift to differentportions of the edge of the lens, thus minimizing the dose to any partof the lens.

The treatment planning embodiments having aspects of the inventioninclude sub-methods for selecting beam paths which substantially avoidirradiating the optic nerve. Unlike the lens and macula, is notsymmetric with respect to the beam azimuthal entry angle. In the exampleshown in FIG. 13 and in further detail in FIG. 16, the optic nerve wasmodeled as a cylindrical cuboidal structure tilted to the center of thepatient's face (extending nasally or medially from retina) by about 20°.See NCRP, “Biological effects and exposure limits for hot particles”,Report No. 130, National Council on Radiation Protection andMeasurements, Bethesda, Md., 1999, which is incorporated by reference.In particular, the method may be employed to determine advantageous orundesirable azimuth angles with respect to optic nerve exposure.

FIGS. 15-17A,B depict the test cases and results of an exemplaryradiation modeling study of varying optic nerve angles with respect tothe posterior sclera, the geometry of the beam cases of the study, andthe anatomic geometry of different optic nerve cases studied. FIG. 15shows the beam angles in the X-Y plane of the eye (azimuth angles θrotating around geometric axis 2082), indicating the relative positionof the entry point of the beam on the pars plana, oriented to propagateto the macula target.

As shown in the example of FIG. 15, a range of 8 space azimuth angles θas beam entry directions were selected as test cases for Monte Carloanalysis (0-315° by 45° increments), thus defining a cone of possibleirradiation directions (an angle of 0° corresponds to the 12 o'clockposition when viewing the patient's treated eye). These angles can bedescribed using a spherical 3D polar coordinate system with the maculaat the origin and the z-axis defining the geometric axis. In all 8 beamazimuthal angles, the X-ray source-to-target distance was assumed to be130 mm, and the polar angle Φ was fixed at 30° from the geometric axis.

FIG. 16 illustrates a range of modeled geometries of the optic nerve asit extends in the medially-posterior direction from retina toward thebrain. A range of 5 possible angles are included, ranging from an upwardextension at +20°, from the horizontal plane to a downward extension at−20° (cranial +; caudal −), as test cases for Monte Carlo simulation.

FIG. 17A shows a plot showing the results of a Monte Carlo tests for thecases shown in FIGS. 15-16, including the mean absorbed dose for thelens, and to the optic nerve as a function of vertical tilt angle. Inthis test, each beam is targeted to deliver fixed dose to the maculartarget of 8 Gy, for a 100 kVp X-ray source having 2-mm Al totalfiltration. The mean dose to the lens was found be insignificant (51 to53 μGy) for all beam directions and optic nerve tilt angles. Withrespect to the optic nerve, from the plot it may be seen that:

(a) For treatment beam azimuthal angles θ between 0° and 180°, the meanoptic nerve doses were also found to be insignificant (47 to 92 μGy) forall vertical optic nerve tilt angles.

(b) For a treatment beam angle of 225°, the doses were very small for anoptic nerve angle of −20° or −10°, rising only slightly to about 0.30 Gyat the optic nerve angle of 0°, but becoming more significant at theoptic nerve angles +10° and +20° (about 0.85 Gy and 1.7 Gyrespectively).

(c) For a treatment beam angle of 270°, the optic nerve doses were atsignificant levels for optic nerve angles of −10°, 0° and +10°.

(d) For a treatment beams angle of 315°, the optic nerve doses were atsignificant levels for optic nerve angles of 0°, +10° and +20°.

It is believed that the patient population will be characterized byangles within the −20° to 0° range (see R Unsold, J DeGroot, and T HNewton; “Images of the optic nerve: anatomic-CT correlation”; AJR Am JRoentgenol 135, 767-773 (1980), which is incorporated by referenceherein).

In addition, FIG. 17B-D are drawings taken from superimposed imagescompiled from CT scans of a human being, the images have been processedelectronically to enhance and define certain tissue contrasts andgraphically represent tissue geometry. FIG. 17B shows a human head,processed to enhance contrast of eye structures relative to bone tissue.FIGS. 17C and D are perspective views of a right and left eyesrespectively, with bone and other orbital tissues removedelectronically, also showing superimposed modeled images of threestereotactic radiation beams focused on a retinal target.

FIG. 17B shows the extent of the optic nerves 350 in frontal aspect. Itmay be seen that both the right and left optic nerves 350 have a path350 a that trends downward (caudally) as well as medially as it extendsbackward to the brain. This data supports one embodiment of aradiotherapy treatment plan as described in detail herein which employexemplary beam azimuth angles θ of about 150°, 180° and 225°, shown asb1, b2, and b3 respectively in FIGS. 15 and 17A (see also FIG. 30A).These are consistent with very low to negligible optic nerve radiationdoses for realistic optic nerve anatomy. These are also consistent withextremely low doses to the lens and cornea, as shown in FIGS. 13 and 14.However, other or additional treatment beam orientations may be selectedwithout departing from the spirit of the invention.

FIGS. 17C-D likewise show the optic nerve path 350 a descending belowthe treatment axis 2820. The three radiation or X-ray beams (beams 1-3)are generally oriented as shown in FIGS. 30A and 43E, entering thesclera adjacent the limbus 26 and propagating upward to target region318 centered approximately on the macula. As can be seen, the beam paths1-3 avoid the optic nerve 350.

FIG. 56E depicts retinal beam patterns on the surface of a retina,depicting an example where a target lesion is irregular ordiscontinuous.

Eye Anatomy and Targeting

FIG. 18 depicts an anatomical targeting method for radiotherapy. Thecentral or geometric axis 2810 of the eye may be defined approximatelyby the eye-guide 2860 (or alternative eye-alignment methods), which insome cases is a lens which fits the curvature of the front of the eye.The geometric axis 2810 of the eye 30 may be defined as perpendicularlyintersecting the cornea surface 35 at the center of limbus 26. In someembodiments, geometric axis 2810 can be the treatment axis, or adistinct treatment axis 2820 may be defined. In the example shown, thetreatment axis 2820 is offset vertically and/or laterally and liesgenerally parallel to the geometric axis 2810, intersecting the fovea318 of the eye (approximately the macular center). In one embodiment,angle Φ is set so that the x-ray beam 1400 travels into the eye at aspot adjacent to the edge of the limbus 26 on the front of the eye,e.g., near the pars plana, so as to have a clearance “c” from limbus tocenter of beam entry point of about 2 to 6 mm). The central axis, insome embodiments, can be assumed to be the axis which is perpendicularto the center of the cornea or limbus and extends directly posterior andanterior to the cornea and to the center of the retina, as discussedpreviously. In some embodiments, the central axis is the treatment axis,about which a radiotherapy device can rotate; this axis can also bereferred to as the system axis. In some embodiments, the treatment axis2820 can be a parallel line to the central axis 2820 and offset from thegeometric axis 2810 by a distance 2850. The treatment axis can intersectthe retina at the macula or the center of a lesion to be treated. Theaxis 2820 can be any axis in any orientation relative to the centralaxis 2810, axis 2810 being continually identified by the guide 2860.Path length 2830 (indicated also as “L3”) is a distance of the pathfollowed by the X-ray beam during propagation from tissue surface to thetreatment target, and is helpful for predicting the dose at theintersection of the retina, as there will be attenuation of energy bythe time the x-rays reach the retina and, to some extent, thisattenuation will be dependent on the beam tissue propagation path length2830. The tissue path length for a selected planned treatment proceduremay be correlated with a measurement of the patient's eye, mostconveniently to the eye axial length, as further described herein indetail with respect to FIGS. 31A-C.

Optic nerve points in the medial (toward the midline) direction as ittravels behind the eye. In addition, it has been demonstrated byinventors herein, that the typical path of the optic nerve is alsoinferior (downward or caudally) from the eye as it travels behind theeye. The example of a multiple-beam stereotactic treatment plan formacular irradiation having aspects of the invention, as depicted in FIG.30A, accounts for the path of the optic nerve in minimizing absorbedradiation dose to this structure. Reference is made to application Ser.No. 12/100,398 filed Apr. 9, 2008 for further description; whichapplication is incorporated by reference.

FIG. 19A is a schematic view of a fundus image on a patient's retinashowing one example of a treatment plan for AMD. The effect of the axisshift on the treatment region of the retina can be seen, the geometricaxis 2810 is offset from is the treatment axis 2820 (centered on thefovea). Also shown are the dimensions defining relationship with theoptic disk, as the treatment plan preferably assures low dosage to thisstructure. FIG. 19A below illustrates data from a study of severalnormal volunteers in which the intersection of the geometric axis withthe retina was determined and related by distance to the fovea and theoptic nerve. In some embodiments, only one shift geometry is used forall patients. Alternatively, a scaled shift geometry may be used basedon one or more patient-specific parameters, such as axial eye length,e.g. determined by an A-scan or OCT. Shown are averages and maxima andminima for the depicted measurements. Also shown is a triangular diagramsummarizing the average shift data to offset the treatment axis from thegeometric axis: x=+1.16 mm temporally, and y=−0.47 mm caudally, and asfurther shown and described with respect to FIG. 43D. Inventors hereinhave demonstrated from clinical data that an exemplary radiotherapytreatment plan having aspects of the invention and incorporatedtreatment axis offsets at or near these values accurately predicts thecenter of a macular target. Reference is made to application Ser. No.12/100,398 filed Apr. 9, 2008 for further description; which applicationis incorporated by reference.

It has been found that the average shift values shown lead tosurprisingly small errors in the population studied, a maximum error of0.20 mm in the horizontal direction and 0.08 mm in the verticaldirection. Thus, when the geometric axis 2810 intersection with theretina is identified using guide 2860, the fovea or a lesion nearby canbe targeted. A treatment plan can therefore be developed. For example, aknown spot on the lens placed on the front of the eye can be determinedand then the axial length can be used to locate the inner limit of theretina. After locating the point (either virtually by a model orvisually through an imaging device) on the retina where the axis of thelens on the eye intersects the retina, any point along the retina suchas a lesion center can be targeted with by the radiation positioningsystem.

FIG. 19B is a perspective view of a virtual model of an eye 30,including a registered retinal image 350, such as an optical coherencetomography (OCT) image, a fundus camera image, or other medical image ofa patient. In this example, the eye model 30 is shown as aligned with aradiotherapy system Z axis, which is collinear with the geometric axis2810 of the eye. Axis 2810 perpendicularly intersects the cornea 35 at acentral point defined by the center of limbus 26, the axis extendingthrough the eye to the retinal pole 340. An X-Y coordinate plane for theeye model 30 is shown centered on the Z axis tangent to the cornea atthe corneal center 35 (see the alignment method example described withrespect to FIGS. 43 A-E).

A subsidiary retinal reference plane X′-Y′ is defined centered on pole340 (in typical patients, the retinal surface plane X′-Y′ may besubstantially parallel to the corneal X-Y plane). A ophthalmologicretinal image may be incorporated into eye model 30, such as OCT image350, for example by capturing an electronic image of a patient to betreated, and geometrically registering the image data with the model(aligning the image data to retinal plane X′-Y′). A convenient scalefactor for sizing image data to the eye model is the eye axial lengthA1, the distance from the anterior corneal center 35 to the surface ofthe retina at pole 340, which may be measured non-invasively by anultrasonic A-scan.

As described further with respect to FIGS. 19A and 43E, a treatment axis2820 may be defined by offsets from pole 340 (δx, δy in the X′ and Y′coordinate plane), the treatment axis intersecting the retina at atreatment target center 318. By incorporating a patient-specific retinalimage 350 into an eye model 30 and registering the image congruently tothe geometry of a radiotherapy treatment plan (e.g., as shown in FIGS.19A and 30A), the relationship between treatment axis 2820 and thepatient's retinal lesion may be visualized by a physician. Radiationtarget parameters of the treatment plan may either be confirmed ormodified, in preparation for treatment.

Eye Models and Treatment Planning

As described herein with respect to FIGS. 3-6, virtual or phantom modelsof anatomy may be employed in treatment planning embodiments havingaspects of the invention. Information such as described with respect toFIGS. 13-19B may be used to construct a virtual or phantom model of theeye having aspects of the invention (e.g., using software and interfaceswith a computer processor). The eye model may represent the eye to betreated and related anatomy.

The model may be based on generalized human ocular anatomy, and may bebased on patient-specific ocular anatomy. Although human ocular geometryis distinctly variable within patient populations, appropriateadjustments and modifications to a generalized eye model may be madetaking into account one or more patient-specific measurements, so as toaccurately represent a particular patient's eye anatomy. For example, avirtual eye model may conveniently and economically include an overallstructure based on generalized human ocular anatomy, which may then beadjusted or scaled by measurements taken from a patient to be treated,such as an A-scan measurement of eye axial length, routine type ofdiagnostic test used in ophthalmology (A-scan ultrasound biometry canprovide, for example, the central or axial eye length from anteriorcorneal surface to retinal surface).

FIGS. 20 and 21 schematically depicts exemplary embodiments of virtualor phantom models of a human eye and adjacent structures, such as may bedigitally defined using conventional software tools, displays andinput/output devices (or by using alternative graphic orrepresentational modalities). A virtual model may include multiplecomponents, which include different representations of the sameanatomical structures. For example, in embodiment shown in FIG. 20, theeye model includes a virtual representation of much of the ocularanatomy shown in FIG. 18, including the relationship between differentanatomical features and eye geometry.

FIG. 21 shows a model 1451 of an X-ray collimator system 1440 includingthe physical parameters that effect the radiation beam characteristics,as applied to a simplified anatomical representation of the anatomy ofFIG. 20. However, in contrast to FIG. 20, the model 1440 of FIG. 21 issimplified, so that the surface of sclera 17 is depicted as aperpendicular planar surface 1430, and retina surface 1435 is likewisedepicted as a plane perpendicular to the beam axis 1400.

Note also that “emission spot” 1420 is depicted in FIG. 21 as a planarsurface of a defined cross-sectional dimension perpendicular to beampath 1400, and represents an idealized X-ray emitting surface emittingphotons through collimator 118. Actual X-ray devices may have an X-rayemitting source having an number of alternative shapes, orientations andconfigurations. For example, the X-ray-emitting electron-beam target ofan linear accelerator source may be high atomic number material alignedin the path to the electron beam and presenting an exit plane which maybe substantially perpendicular the collimated X-ray beam 1400.Alternatively, the target anode material of an commercial orthovoltageX-ray tube may comprise a surface at a substantial angle to thecollimated X-ray beam 1400, the output X-rays being emitted through awindow (e.g., thin Be sheet) oriented in a generally transversedirection to the cathode beam impinging on the anode surface. The anodematerial may be formed to have a planar surface, or a truncated conicalsurface in the case of a rotating anode. To simplify the model 1440, theeffective X-ray emission spot 1420 from the perspective of aperture 1405may be represented as a disk of defined diameter orientedperpendicularly to beam 1400 and uniformly emitting X-rays of a certaininitial spectrum. For convenience, such an emission source 1420 isreferred to herein as an “anode” or “anode spot” without loss ofgenerality.

Likewise, the aperture 1405 is represented in FIGS. 21-30 as singlecircular opening, but need not be circular and need not comprise asingle opening. See for example, collimator embodiments described inSer. No. 11/873,386 filed Oct. 16, 2007, which is incorporated byreference and in the micro-fractionated patterns shown in FIGS. 55A-Dherein. Where an collimator exit opening and/or projected radiationbeam-spot on a tissue surface or target plane is non-circular(elliptical, rectangular, elongate, irregular or the like), the diametermay be conveniently considered to be a selected geometricallycharacteristic dimension, such as maximum width, a major or minor axis,a mean width or the like.

A model such as FIG. 21 permits convenient modeling of photon energyspectral change as the beam propagates from anode to treatment target.The initial spectra emitted by anode spot 1420 may pass through a filter1423 which shifts the spectrum to a higher mean photon energy byabsorbing predominately lower energy photons (see FIG. 8). The effectivefilter 1423 may comprise any device structure material in the beam path(inherent filtration, e.g., an X-ray tube window, a laser beacondeflection mirror, aperture covering, or the like) and any additionalfilter material positioned for this purpose (e.g., one or more aluminumplates of selected thickness mounted at a selected position in along theaxis of collimator 118).

A filter for penetrating radiation is often characterized by itsabsorption properties scaled relative to a half-value-layers orhalf-value thickness (HVL), related to mean free path of a photon orparticle. An HVL may be defined as the thickness of specified materialwhich reduces the intensity of a particular input radiation spectrumentering the material by half. However, a filter element need not be anintegral HVL and may be of any selected thickness. Likewise, a filterelement need not be of a single or uniform material. For example,filters may have a series of layers, such as layers in decreasing orderof atomic number such as tin, copper, and aluminum layers in thedirection of propagation. Although the examples described may havefilters of uniform cross-sectional thickness or composition, inalternative embodiments, a filter may be non-uniform with respect to thebeam cross-section, so as to produce a spectral variation from one sidethe beam to another (wedge shaped), radially variation about a center,or other variable distribution.

The filtered spectrum is further “hardened” by upward shift in meanphoton energy as it propagates along tissue path L3 of eye 30 towardsretina plane 1435 (“tissue hardened spectrum”, see FIG. 12). As isfurther described with respect to FIGS. 22-29, the intersection of beam1400 with retina 1435 (“retinal target plane”) may be represented inthis simplified model as a circular central 1441 and a concentricpenumbra or “isodose fall off” margin 1442. However, in alternativeembodiments, the beam-spot geometry (1441, 1442) may be configured to benon-circular.

It is apparent that the relevant anatomical structure can be definedmathematically and geometrically, optionally including convenientsimplifications and generalizations, without loss of utility in planningand predicting radiotherapy treatment.

Empirically and/or theoretically determined radiation beamcharacteristics and human tissue characteristics may be correlated withthe eye model to allow modeling of radiation transmission and absorptionalong a beam propagation path. For example radiation propagation andabsorption through tissue may be simulated employing software such asthe Monte Carlo Radiation Transport Code developed by Los AlamosNational Laboratory. As shown in FIG. 20, a virtual model may include ageometric representation of position of the optic nerve extendingposteriorly from the optic disk of the retina (in this examplecharacterized by angle π), which is useful in determining beampropagation paths which minimize dosage to the optic nerve, such as fromthe portion of applied radiation passing through and beyond a treatmenttarget adjacent the macula.

In the examples shown in FIGS. 20 and 21, the virtual or phantom eyemodel 1440, 1450 is configured to represent a narrowly collimatedexternal radiation beam directed to enter an exposed scleral surface 17,such as the pars plana 1430, and propagate to the surface of the retina1435 at or near the macula 318. See co-invented application Ser. No.12/100,398 filed Apr. 9, 2008 (which is incorporated herein byreference) for further description of methods having aspects of theinvention for determining suitable beam paths for ocular treatments, andin particular, beam paths which may be used to treat a macular region,while minimizing absorbed dosage to such structures as the lens andoptic nerve.

In an embodiment of a treatment planning method having aspects of theinvention, beam tissue path length L3 is determined (i.e., radiationbeam distance through tissue from air entry point to treatment target),and the path length is in turn employed with a radiation transport modelto account for reduction in beam strength and spectral profile as itpasses through tissue. This permits determination the dosage at thetarget relative to the air kerma beam dosage. In actual treatment, themagnitude of radiation can then be adjusted to provide an accuratelypredictable absorbed dosage at the target (e.g., by adjusting theradiation duration).

As one example, it has been shown in studies conducted by inventorsherein that, for a treatment plan to irradiate the macular region via abeam entry point near the pars plana, that the tissue path length of awide range of patients can be accurately predicted using a virtual modeland a single A-scan measurement of a patient's ocular axial length.Indeed, an linear approximation can give good results for a particulartreatment plan, such as a formula PL(mm)=AL(mm)−k, where k is a constantsuch as about 3. See further description with respect to FIGS. 31A-C. Inaddition, patient-specific imagery may be incorporated into the eyemodel, such as is schematically depicted in FIG. 19. In one embodiment,a fundus image is obtained from a patient prior to radiotherapytreatment, the image may then be scaled in proportion to a patientmeasurement such as ocular axial length, the image being aligned andsuperimposed on the virtual model.

An eye model may be used in planning treatment, as is depicted in FIG.30A, such as by determining a treatment axis 19 with reference to aradiotherapy system reference 18, and defining one or more radiationtarget regions 318 suited to the disease being treated. One or moreradiation beam paths 1400 may also be defined with reference to themodel. In the example shown, three stereotactic beam paths 1400 a-1400 care planned so as to be coincident adjacent target region 318 centeredon treatment axis 19. Planned positions/orientation of X-ray beam 1400may likewise be superimposed on the model by correlation of the modelcoordinate system with the planned system coordinates. A image displayedto an operator/physician may thus include model data; scaled andregistered fundus image data (and/or other medical image data); togetherwith planned radiotherapy beam geometry data. Among other things, thispermits a physician to confirm that the planned treatment is appropriatefor the lesion of the patient, as seen in the fundus image.

The model may be used to determine patient-specific parameters relevantto radiation propagation, such as a tissue path length along a beam path1400 to a target region 318 to apply radiation dosage to a target beamspot 1441 (see FIG. 21). In this manner, an eye model having aspects ofthe invention may be used to compile a patient-specific treatment planwhich accurately predicts radiation dosage levels and distribution in atarget region 318 as shown in FIG. 20, and which accurately predictsradiation dosage distribution relative to anatomical structures such asthe lens 36 and optic nerve 32 see optic disk 3260 in FIG. 30B). See forexample the retinal dose map of FIGS. 30C-D. Data from suchradiographically-measured and/or computationally simulated dosedistribution may be incorporated and registering with a phantom orvirtual model. Planned radiation beam geometry (See FIGS. 20 and 30A)may then be included in the model as virtually-projected radiation beams1400 from a virtual radiation source, and used to simulate dosedeposition at a target region 318 in the phantom model.

A combination of anode size, anode-to-target distance and collimatorlength may be selected by methods having aspects of the invention for anX-ray source providing a tightly collimated beam spot of appropriatemaximal intensity, sized to a selected target region dimension, andhaving sharply defining penumbra or area of dosage fall-off surroundingthe beam spot. A combination of X-ray tube field potential and filterdimensions may be selected by methods having aspects of the inventionwhich provides a favorable ratio of radiation dosage at a scleral entrypoint to target region (pre-target absorption or “tissue hardening”),while permitting rapid attenuation of beam dosage beyond the targetregion, such as be absorption in orbital skull bone (post-targetabsorption). See co-invented application Ser. No. 12/100,398 filed Apr.9, 2008 (which is incorporated herein by reference) for furtherdescription of the characteristics of radiotherapy beams andconfiguration of X-ray treatment devices having aspects of theinvention. The embodiments have selected parameters which provideradiation treatment beam characteristics which are particularly wellsuited to the treatment of ocular lesions, including lesion of theretina such as occur in AMD.

Dependence of Penumbra and Dose Distribution on Anode Spot Size

FIGS. 22 and 23 illustrate a study in which theoretical anodes (viaMonte Carlo simulation) of different sizes were utilized to determine,in connection with the beam penumbra, effects of different sized anodesfor usage in the radiotherapy system. X-ray tubes are commerciallyavailable providing a wide range of anode spot sizes (focal spot size)1420. The term “anode size” as used herein is the characteristiceffective X-ray emitting anode spot dimension as seen from the vantageof the emitted beam axis. The physical anode, such as a fixed plate orrotating plate of target material (e.g., tungsten or tungsten alloy) istypically set at an angle to the impinging accelerated electron streamfrom cathode (e.g., about 10 to 20 degrees), and the useful X-ray beamis allowed to escape through a tube window (e.g., thin Be plate) atapproximately right angle to the impinging cathode electrons.

The anode is considered the radiation emitting source of a typical X-raytube, and its size, structure, and cathode focusing devices have rolesin penumbra determinations. For example, an idealized point source maybe approximated by a anode with a largest diameter of equal to or lessthan about 1 mm; point sources can deliver the highest quality beam withthe tightest penumbra 1442. Less optimal are sources with anodes greaterthan about 1 mm; for example, 2-mm, 3-mm, 4-mm, or 5-mm sources can alsobe used in connection with the embodiments described herein.

FIGS. 22A-22D depicts a virtual model showing an exemplary range of fouranode sizes, and depicting an exemplary collimator configurationarranged to direct an X-ray beam 1400 at a simulated eye 30′. Thisvirtual model assumes for convenience that both the scleral surface 1430and the retinal target surface 1435 are planes perpendicular to theX-ray beam axis. The X-ray tube potential, filter characteristics,anode-to-target distance, collimator length, collimator exitdiameter/shape, and tissue path length may all be selected to model adesired treatment beam and radiotherapy plan.

In the example shown in FIGS. 22A-22D, the collimator configuration is aconstant typical example, the only variation being anode size, so as todemonstrate the effect of the anode size independent of other factors.The X-ray tube is positioned to have the anode 1420 about 150 mm fromthe retinal target 1435, penetrating through about 20 mm anterior eyetissue to the retinal target, a tissue path length consistent with themore anatomically complex model shown in FIG. 20, and with the typicalrange of patient anatomy. The collimator has a 2.5 mm diameter circularexit aperture 1425 positioned about 75 mm from the anode 1420.

The examples of anode sizes are: (A) 0.0 mm (point source); (B) 0.4 mm;(C) 1.0 mm; and (D) 5.5 mm. The characteristics are illustrated by raytracing, idealized to assume unscattered and undeflected propagationthrough the collimator exit aperture from each point on a circular anodesurface to the retinal target plane. For each anode diameter, (a) across section along the axis of beam 1400 is shown projected to (b) across section perpendicular to the beam path taken at the retinal plane1435 and illustrating the beam spot 1440 in the target region. It may beseen in each case, the target region is illustrated showing by adarkly-shaded central spot 1441 (fully illuminated by the anode) and alightly-shaded annular penumbra region 1442 (partially shadowed by thecollimator aperture).

It may be seen that the relative width of the annular penumbra regionincreases progressively as the anode size increases. In the case of theidealized point source (anode diameter=0.0), the annular width is zero.For the largest anode shown (anode diameter=5.5 mm), the annularpenumbra region covers the entire illuminated area. Clearly, there areadvantages to a small anode, when a tightly-defined dose region isdesired. Although the models of FIG. 22 might be interpreted to suggestthat the smallest possible anode would give the optimum therapeutic beamspot, the model can be interpreted in light of the physicalcharacteristics of a typical X-ray source.

The anode is also a major determinant of the x-ray flux. The heatgenerated by the anode is the major limiting factor in the ultimate fluxwhich can be achieved by the x-ray source. To the extent the anode canbe cooled, the x-ray flux can be increased accordingly. This is part ofthe trade-off in penumbra; larger anodes can tolerate larger currentsdue to their larger thermal mass. X-ray output is related to current sohigher current for a lower temperature allows a greater x-ray flux. Insome embodiments, rotating anode sources are used so that the anode is“cooled” by virtue of the anode being moved to different points withtime. While technical features such as liquid cooling, rotating anodes,and the like can alleviate anode heat concentration and increaseavailable X-ray source intensity for a given anode size, there remaintechnical trade-offs to be considered in anode parameter selection.These include the desired dose rate at the target (Gy/min), filterthickness (reduce flux), anode-to-target distance (inverse-square beamdivergence), collimator configuration parameters effecting beamapplication (e.g., exit aperture size, shape and distance from anode),and particular clinical goals and requirements.

FIG. 23 is a plot showing the results of a Monte Carlo computationalsimulation (see description re FIGS. 10-17) for four anode size testconfigurations generally similar to those shown in FIG. 20. Thecomputational simulation accounts for radiation propagation effects,such as scattering in tissue, and provides additional description of theeffect of X-ray source focal spot or anode size on the resulting doseprofile across the macula target. Cross sectional profile to theabsorbed dose to the macula target for a 100 kVp x-ray beam as afunction of focal spot size. A collimator was selected to createapproximately a 4.0 mm beamspot, and too simply the MCNP geometricalsetup, a non-clinical normally incident beam angle is assumed. Absorbeddose profiles at the center of macula are shown for focal spot sizes of0.0, 0.4, 1.0, and 5.5 mm, respectively, for a targeted central dose of8 Gy. Vertical lines are placed at +2 mm and −2 mm radius, to representthe anatomic size of a macular lesion target region of 4 mm diameter.

In FIG. 23, no significant differences in the dose profile are seen forfocal spot sizes from 0.0 to 1.0 mm, and the penumbra of each extendsoutward 1 of 2 mm radially. For the larger 5.5 mm spot size, doseuniformity is significantly reduced within the target region, such thatthe dose at the edges of the target are only one-half that at center,and the penumbra extends outward at slightly higher dose values thanseen for the smaller spot sizes. Dose coefficients in the central regionwere estimated to be 7.8, 7.7, and 7.7 Gy/Gy for spot sizes of 0, 0.4,and 1.0 mm, respectively, where the reference air kerma value is againset at 100 cm from the x-ray source. The dose coefficient for the 5.5 mmspot size beam is 18 Gy/Gy, thus requiring only ˜42% of the integratedtube current (mAs) needed to deliver 8 Gy central dose using the smallerfocal spot sizes. However, its dose uniformity is significantly reducedwithin the macula target. As can be seen in the graph in FIG. 23, the0.0 mm anode is the ideal case of a point source, and there is acorresponding sharp drop-off of dose; as the collimator increases insize to 1.0 mm, there is a very limited effect or change from the idealcase. However, when the anode reaches 5.5 mm, as can be seen in thefigure, there is a much broader spread of dose, or penumbra. The samecollimator that creates essentially a 4 mm beamspot in the O-mm casecreates over a 5-mm beamspot when it is 5.5 mm in size. In essence, alarger penumbra is realized as the anode size increases.

The sharpness of the falloff of the target spot from full dose to zerodose is measured by the penumbra. Penumbra represents the portion of thetarget that does not “see” the entire anode focal spot and hence doesnot receive the full dose. The sharper the penumbra, the tighter andmore conformal the dose can be delivered. One metric that may be used tocharacterize the dose profile and size of an the X-ray beam spot andeffective penumbra dimension makes use of isodose contours, convenientlyexpressed as a percentage of a maximum central region dose. Penumbra maybe given an empirically convenient definition as the distance betweenthe 80% the 20% isodose lines (the 80-20 penumbra) and the distancebetween the 90% and 10% isodose lines (the 90-10 penumbra).

The plots of FIG. 23 illustrate such usage. The left hand of the plotincludes a secondary vertical axis depicting percent of central dose(e.g., an exemplary clinical plan dose of 8 Gy per beam). Severalgeneralized features may be seen in a comparison of the four curves inthis example according to isodose levels:

(a) Below about the 10% dose level, all the anode plot curves show acertain amount of spreading or scatter, as indicated by the generallyshallow gradient of the curves, although the larger anodes produce agreater spreading of dose.

(b) At about the 20% dose level, all four anode plot curves are nearlysuperimposed (nearly the same radial dimension) regardless of anode sizeand all have a fairly steep downward gradient.

(c) Between about 80% and about 90%, the curves for 0.0, 0.4 and 1.0 mmanodes have vary similar radial dimensions, whereas the 5.5 mm anode hasa substantially smaller radial dimension.

Thus a delimiting value may be conveniently selected of about 10-20% asa useful measure of the maximum penumbra radius in the example shown,for purposes of comparison of different beam parameters. Similarly adelimiting value may be conveniently selected of about 80-90% as auseful measure of the inner boundary of the penumbra or central beamspotradius. In the example of the 1.0 mm anode curve in FIG. 23, the 80%isodose contour is shown to have a radius of about 2.0 mm and the 20%isodose contour has a 2.6 mm radius, then the 80-20 penumbra is2.6−2.0=0.6 mm, or expressed as a percentage 0.6/2.0=30%.

An alternative meaning of the term penumbra that may be used in thecontext of collimated external beam applications so as to include theeffects of beam inverse-square divergence in combination with theeffects of anode size, scattering and the like. In this usage, outermargin of the penumbra (e.g., the 20% isodose contour) is compared withthe collimator exit aperture. For example, if it is assumed that the 1.0mm anode curve in FIG. 23 was emitted through a collimator aperture of2.5 mm diameter (1.25 mm radius), and the 20% isodose contour has a 5.2mm diameter (2.6 mm radius), then the penumbra based on collimatoraperture is 2.60−1.25=1.35 mm, or expressed as a percentage1.35/1.25=108%.

It can be seen in the example of FIG. 23, that while each of the smalleranode sizes (0.0, 0.4 and 1.0 mm) deposit about 80% or more of themaximum dose within the indicated 4 mm diameter target region, the 5.5mm anode deposits a profile with a substantial “undertreated” area withthe 4 mm diameter target region, dropping to about 50% dose lever at the2 mm radius. Stated another way, only the smaller anode sizes in thisexample configuration provide a fairly uniform dose profile (at least80% maximum) within the central target region, changing to a steepisodose drop-off (penumbra gradient) to a 10%-20% dose level within asmall penumbra radius.

A clinical objective certain embodiments of methods and devicesdescribed in detail herein is to achieve a therapeutic dose level withinparticular dimensions of a target lesion (e.g., AMD lesion), whileminimizing dosage to sensitive or vulnerable structures adjacent to thetarget lesion (e.g., optic disk and nerve). For example, the treatmentplan may provide a therapeutic dose to the 4 mm diameter macular targetwhile avoiding undue dose to the optic disk, the margin of which may beonly about 1.5-2.5 mm from the edge of the target region. FIGS. 22 and23 demonstrate that selection of a small anode is useful in achievingthis objective, in conjunction with suitable selection of other X-raysource and collimation parameters. In addition, a sharp dose drop-offadvantageously limits the dose to other structures remote from thetarget volume but adjacent the beam axis, such as portions of the lensand cornea adjacent a scleral beam entry point.

FIG. 24A depicts the results of a single collimated x-ray beam 2600 asdepicted at the collimator aperture. FIG. 24B depicts the beam 2620after it has penetrated through approximately 20 mm of solid waterphantom material (modeling an eye); the shaping collimator isapproximately 50 mm from the surface model. The beamspot was captured onradiochromic film at the 20 mm target depth. As can be seen in FIG. 24B,there is a small penumbra width 2610 about an original beam width 2620after penetration through the eye which is less than about 10% of thediameter of the shaping beam shown in FIG. 24A. These data incorporateboth divergence as well as isodose drop off from scatter and reveal thatfor a collimator within about 100 mm of the target, the penumbra can bevery small. The beam energy in this example is approximately 80 keV.

FIG. 24C depicts a graphical representation of the penumbra frommeasurements within an x-ray detection films at two different locationsof a solid water eye model. Delta 2650 represents the absorption in theenergy between the surface and the depth as recorded by x-ray sensitivefilm. This models the sclera-to-macula tissue path.

FIG. 24C shows quantitatively the rapid falloff on the sides of thebeam. The tails seen in 2640 versus 2630 indicate a small degree ofpenumbra effect as the beam loses energy through the eye. Note that thewidth of the sides (the penumbral region) is small compared to thecentral, full-dose region. These measured results closely match MonteCarlo simulations shown in FIG. 23. Also evident from the plots is thatthe macular dose from the single example beam is roughly one-third thedose at the sclera. This dose ratio provides that for a three portstereotactic treatment of a macular target, the scleral and maculardoses would be similar in magnitude.

FIGS. 25A-25D schematically depicts a model similar to that of FIGS.22A-D, comparing the same four different examples of source anode sizes1420, but for collimator configurations having apertures sized toproduce a constant central beam-spot size 1441 at the target plane. Notethat in certain embodiments of radiotherapy methods and systems havingaspects of the invention, a treatment plan is tailored to applyradiation to a lesion of known size, and a beam spot may projected on atarget plane having a pre-determined target region diameter 1441, withinwhich there may be applied a generally uniform dosage, surrounded by aannular region of rapidly-falling dose intensity (penumbra 1442). Thusit is useful to also compare the effect of variation in anode size in amodel in which the collimator configuration is adjusted so that eachexample has a constant central beam-spot size (e.g., corresponding atarget region). Similarly, comparisons may be useful in which otherparameters are held constant, such as collimator aspect ratio, totalX-ray flux, and the like.

In the examples of FIGS. 25A-25D, the central beam spot 1441 is held at4 mm diameter by adjustment of the diameter of aperture 1405 for eachanode size example. The results shown are generally similar to those ofFIGS. 22A-D, with the exception of the penumbra for the largest anodesize (5.5 mm) for which the penumbra radius is dramatically larger, dueto the relatively large aperture needed to project a 4 mm center spot(region illuminated by the entire anode surface). The width of thesurrounding annular region which is only partially illuminated by theanode surface is thus proportional to anode size (for clarity in theexamples, it is made equal to anode size due to the arbitrary collimatorgeometry, in which L1=L2+L3, see FIG. 21).

Effect of Other Collimator Parameters on Penumbra.

FIGS. 26A-26C schematically depicts a model similar to that of FIG. 21,comparing graphically the effect of three different examples ofanode-to-target distance (L0) on penumbra, for collimator configurationshaving apertures sized to produce a constant central beam-spot size atthe target plane. In order to show the effect of anode distanceindependent of collimator to target distance, in the examples shown thecollimator exit plane to target distance (L2+L3 in FIG. 21) is heldconstant (in this example, about 75 mm). As in the examples of FIGS.25A-D, the aperture diameter 1405 is adjusted in each example tomaintain the central beam spot size constant (in this example, 4 mm).

It may be readily seen that the penumbra region 1442 decreases as theanode-to-target distance increases, for a given central spot size.However, the anode-to-target distance places is an important parameterin determining central spot does intensity. For a given X-ray sourcecondition providing a particular X-ray input intensity, theanode-to-target distance places a physical limit on the beam spotcentral radiation intensity, the intensity at the center of a beam spot.This is as a consequence of the inverse-square law governing thedecrease in radiation intensity with distance and divergence of acollimated beam.

In determining a treatment plan by methods having aspects of theinvention, X-ray source parameters may be selected determining aparticular beam input intensity and spectra. An anode-to-target distancemay then be selected, so as to provide desired central beam-spot doseintensity, permitting a desired target radiation dose within a selectedtreatment time interval. In certain exemplary embodiments having aspectsof the invention, a treatment plan and corresponding device operationare determined so as to deliver sequential stereotactic beam treatmentsin which the anode-to-target distance is held constant for each beamposition.

For such a selected anode-to-target distance, the size of the penumbrais directly related to geometrical issues with the collimation and thesize of the anode focal spot. The smaller the anode focal spot is, thesmaller the penumbra will be. Similarly, the closer the beam-definingfinal aperture is to the patient, the sharper (smaller) the penumbra.Embodiments of radiotherapy systems having aspects of the inventioninclude selected anode sizes and collimator lengths to provide abeamspot with a desired central radiation intensity while having a smallpenumbra.

FIGS. 27A-27C schematically depicts a model similar to that of FIG. 21,comparing graphically the effect of three different examples ofcollimator exit plane-to-target distance (L2+L3 in FIG. 21) on penumbra1442, for source configurations having constant anode-to-targetdistances (L0), and apertures 1405 sized to produce a constant centralbeam-spot size 1441 at the target plane 1435. Consequently each examplehas a different distance of collimator exit from the eye surface (L2 inFIG. 21), as it is assumed that the tissue path length is the same ineach example. Note that these examples, like those of FIG. 22, areillustrated by ray tracing, the characteristics idealized to assumeunscattered and undeflected propagation through the collimator exitaperture from each point on a circular anode surface to the retinaltarget plane.

Thus the differences in the penumbra and beam spot profiles between theexamples FIGS. 27A-C are due to the effect of collimator length, otherfactors being fixed. It may be readily seen that the penumbra sizedecreases as the collimator length increases (L1 increases for a fixedL0, per FIG. 21). It may be seen from the geometry, that the penumbra isdecreased as the collimator length increases and the beam issuccessively delimited closer to the target plane.

For example, it in certain embodiments of radiotherapy systems havingaspects of the invention, the collimator aperture may be positionedclose to the tissue surface (e.g., with a small clearance from thesclera, or alternatively, in contact with the sclera or nearly so) tominimize the annular penumbra at the target region. See examples ofFIGS. 24A-D described herein.

Alternatively and advantageously, in the exemplary embodiments ofradiotherapy systems that are described in detail herein, a relativelysmall anode and suitable exit aperture may be included to reducepenumbra, while patient comfort and operating convenience may beprovided by providing a selected clearance distance between collimatorstructure and the patient's body (this distance is indicated as L2 inFIG. 21, and is shown as about 55 mm in the example of FIG. 22). Aclearance distance L2 may be selected for operating convenience andpatient comfort, and this is particularly advantageous when treatment isadministered using a automated stereotactic positioning system (seeFIGS. 37-38), which adjusts the collimator orientation throughsuccessive beam positions, while moving structure near a patient's face(See, for example, FIG. 37).

Note that embodiments of positioning systems having aspects of theinvention as shown in FIGS. 37 and 38 may be used so as to solely rotatethe collimator 118 about a single axis (e.g., θ axis 2820) withoutfurther movement of other degrees of freedom between successivestereotactic beam positions. This 1-DOF stereotactic procedure isadvantageous in operational simplicity, in intuitive appeal to bothoperator and patient, and in increased precision of movement. Outerportion 118 b may be moved manually or by an automated mechanism, suchas by action of a actuator providing linearly-aligned extension movement(not shown), e.g., a linear or helical electro-mechanical actuatormechanism such as used in camera zoom lenses.

The example of FIG. 28 is shown in the form of a “zoom-lens”-likemounting of an exit-aperture disk on a collimator body. The telescoping,tube-mounted structure shown is exemplary only, and it should be notedthat in alternative embodiments may be made with substantially differentstructure without departing from the spirit of the invention. Forexample, outer potion 118 b need not be directly mounted to base portion118 a, but may be independently supported, the independent supportconfigured to permit movement of aperture 1405 distally and axially awayfrom anode 1420, so as to increase distance L1. In this fashion, certainembodiments may be made which omit base portion 118 a, such as where anydesired beam conditioning components (e.g., choke plate, filter, strayradiation shielding) are independently provided.

Note that an extensible collimator may be included as, in effect, anadditional degree of freedom for a X-ray source positioned, such asshown in FIGS. 33-38. For example, it in certain embodiments ofradiotherapy systems having aspects of the invention, the X-ray source112 and retracted collimator 118′ may be first positioned in one or moredegrees of freedom, for example in the X-Y-Z volume and with a selectedpolar angle Φ. The azimuth angle θ may be selected in sequence for eachbeam position (e.g., b1-b2-b3 in FIG. 17A-B). For each beam position,prior to emission of radiation but after positioning the X-ray sourceand collimator, extensible outer portion 118 b of collimator 118′ in maybe extended axially (extension 118 c) or “zoomed” so as to placecollimator exit 1405 a selected distance from the surface of the eye 30.Following emission of radiation, the extensible outer portion 118 b maybe retracted prior to repositioning of the X-ray source and collimator.

Note that collimator 118′, and/or the system in which it is used, maycontain detectors and safety mechanisms permitting a close approach tosensitive tissue. For example, aperture 1405 may have a covering ofcompliant biocompatible material 119 so as to cushion and protect thesclera or other ocular structures, permitting operation close to theface or permitting safe eye contact. Likewise proximity detectors and/orservo-controls may be used to automatically maintain a selectednon-contact clearance from tissue, or in the alternative, to limit anyforce applied on tissue contact.

In addition, in certain embodiments, aperture 1405 does not have asimple circular opening arranged symmetrically about the axis of beam1400. See for example, the various “shaped beam” collimator embodimentsdescribed in priority application U.S. Ser. No. 12/100,398 filed Apr. 9,2008, which is incorporated by reference. These embodiments provideX-ray treatment beam cross-sections having asymmetrical or non-uniformbeam patterns, e.g., donut-shaped, elongate, crescent-shaped and/orspeckled or micro-fractionated patterns. The outer portion collimatorportion 118 b may be configured to be controllably rotated about axis1400, in addition or alternatively to being extended along axis 1400, soas to align an asymmetrical beam cross section with the desired targetregion.

For example, a collimator embodiment 118 comprises aperture 1405 whichprovides crescent-shaped beam exit pattern configured to minimize dosageto the optic nerve adjacent a nearby retinal treatment target. The beampattern created by aperture 1405 includes a maximal dose-intensityregion which is shaped to match a retinal target lesion, and acorresponding minimal dose-intensity region of the pattern is shaped toalign with the optic disk, thereby sparing that structure. The aperture1405 may be rotated as mounted in the outer portion 118 b, so as toalign a minimal-intensity region of the pattern with the optic disk.Rotation of portion 118 b may thus compensate for overall rotation ofthe collimator during repositioning of the X-ray source for successivestereotactic treatments.

FIG. 29A is a plot showing the results of a Monte Carlo computationalsimulation for absorption of X-ray energy in a configuration generallysimilar to that shown in FIG. 21. See description above of computationalsimulations such as Monte Carlo simulations with respect to FIGS. 12-17and 23. The computational simulation accounts for radiation propagationeffects, such as scattering in tissue, on the resulting dose profileacross a retinal target. Cross sectional profile to the absorbed dose tothe macula target for a 100 kVp X-ray beam. A collimator was selected tocreate approximately a 4.0 mm beamspot, and too simplify the MCNPgeometrical setup, a non-clinical normally incident beam angle isassumed. The absorbed dose profile at the center of macula is shown forX-ray tube anode focal spot size of 1.0 mm, positioned 100 mm from thetarget, for a targeted central dose of 8 Gy. Vertical lines 1441 areplaced at +2 mm and −2 mm radius, delineating also the 80% isodose inthis model. The ±2 mm region approximates the anatomic size of a macularlesion target region of 4 mm diameter. The penumbra 1442 is indicated asbounded by the 20% isodose, with low dose or “scatter” region 1443adjacent the penumbra margin.

In FIG. 29A, the dose coefficient in the central region was estimated tobe 7.7 Gy/Gy, where the reference air kerma value is again set at 100 cmfrom the x-ray source. The sharpness of the falloff of the target spotfrom full dose to zero or very low dose is measured by the penumbra.Penumbra represents the portion of the target that does not “see” theentire anode focal spot and hence does not receive the full dose. Thesharper the penumbra, the tighter and more conformal the dose can bedelivered. One metric that may be used to characterize the dose profileand size of an the X-ray beam spot and effective penumbra dimensionmakes use of isodose contours, conveniently expressed as a percentage ofa maximum central region dose.

Penumbra may be given an empirically convenient definition as thedistance between the 80% the 20% isodose lines (the 80-20 penumbra) andthe distance between the 90% and 10% isodose lines (the 90-10 penumbra).The 80-20 penumbra in FIG. 13A is indicated to be less than 1 mm inextent for the 4 mm beamspot diameter. Note that the model also shows adegree of scattered dosage at 10% of less of the maximum dose intensity,extending outward beyond the 20% isodose line, trailing off thereafterto a low level of dosage (>1% of maximum) as the radius from targetincreases.

For purposes of comparison, FIG. 29B shows a plot of measured doseintensity at retinal depth for an X-ray/collimator configurationcomparable to that of FIG. 29A. In this example, a radiographic film wasplace behind an approximately 20 mm thickness of “solid water” typewater-equivalent radiographic phantom material, to simulate the tissuethickness depth of the retina. The optical density of the film, exposedto about 10 Gy of absorbed X-ray dose, was converted mathematically toan equivalent absorbed dosage. It may be observed that the general shapeof the beamspot and penumbra is very similar to that shown in the MonteCarlo simulation of FIG. 29A. However, no bolus of scatter immediatelybeyond the penumbra (believed to be an artifact) is observed in themeasurements, the dosage level instead dropping consistently and rapidlyto a low level beyond the 20% isodose (“measured scatter”). Thisdistinction between the modeled scatter and the measured scatter isindicated also in FIG. 13A by a dashed line. Note that although themeasured penumbra and scatter region is smoothly and consistentlycharacterized in the radiographic measurements of FIG. 29B, the centralbeamspot is depicted somewhat irregularly, apparently due to saturationexposure of the film at maximum dosage.

Stereotactic Beam Targeting

FIG. 30A is a frontal view of an eye as seen aligned with a systemreference axis 18 (temporal to right, nasal to left), and depictingstereotactic X-ray treatment beam geometry, such as described in FIG.18. Once reference axis 18 is identified (e.g., geometric axis 2810),treatment may be carried out by a device oriented with respect axis 18.Alternatively, a distinct axis 19 may be defined with respect to axis18, for example by a shift of distance dy and dx, so that axis 19intersects treatment target 318 positioned off-axis with respect to axis18. Axis 19 may be called the “treatment” axis. Based on straightforwardgeometry, the device 312 can now be positioned so that its beam axis 311intersects treatment axis 19 at tissue target 318. Axis 18 may be usedto define one or more correlated geometric axes in the externalcoordinate system, and to define one or more additional intersectionpoints with respect to beam 311. Note for treatment targets lying onreference axis 18, offset “d” may be about zero, and for treatmentdelivered through or to the cornea, angle “Φ” may approach zero. Theillustrated example is of an embodiment in which the alignment system iscoupled to a treatment system adapted for orthovoltage X-ray treatmentof a region of the retina generally including the macula.

FIG. 30A can be correlated with FIGS. 15-18 and 20 which show relatedeye anatomy and the geometry of associated eye alignment-radiationtreatment system 300. As shown in FIG. 30A, although a single beam axis1400 may be employed, a plurality of beam axes may be defined in whichtwo or more treatment beams are aimed to impinge on target 318stereotactically. Treatment axis 19 may be chosen to intersect aselected target 318 within the eye, and employed as a reference toorient two or more treatment beams aimed to impinge on target 318stereotactically.

In the example of FIG. 30A, treatment axis 19 is chosen to intersect aselected target 318 within the eye, and employed as a reference toorient three treatment beams projected along three different beam axes1400 a, 1400 b and 1400 c, the beam axes defined so as to each impingeson target 318 from a different direction. Multiple beams may beprojected simultaneously, or sequentially, with intervening periods ofno treatment if desired. Likewise, multiple beams may be provided bymultiple separately-positioned treatment devices. However, a preferredembodiment employs a single treatment device 312 (e.g. a collimatedorthovoltage X-ray source), which is sequentially repositioned bypositioning device 310 to administer treatment in sequential doses alongeach of a plurality of beam axes, such as axes 1400 a, 1400 b and 1400c. The beam axes each have a different respective point of entry intothe body surface (311 a, 311 b and 311 c respectively) and each followsa different tissue path leading to target 318. Likewise each beamfollows a different tissue path for any propagation beyond target 318.In this way, treatment beam dosage penetrating tissue remote from target318 may be minimized relative to the dosage received at target 318.

Note that the number of stereotactic beam paths selected (for emissioneither sequentially or simultaneously) may be selected from aconsiderable range to achieve treatment goals. FIGS. 30A-B illustrate a3-beam pattern example (1400 a-c), and device embodiments described indetail herein (e.g., FIGS. 37-38) can conveniently administer such apattern in sequence. However, alternative devices having aspects of theinvention may have multiple X-ray source and/or collimators configuredto administer such a pattern simultaneously. In other alternatives,treatment goals may be achieved with a single beam path 1400. In stillfurther alternatives, treatment goals may be achieved with a number ofbeams exceeding three (e.g., 1 to n beams).

In yet further embodiments, a beam path 1400 i may be continuously movedstereotactically during X-ray emission over a beam track on the sclera(or other body surface) having a selected scope or range, so that whilethe entry region for radiation is spread out along the surface track soas to reduce local tissue dose (see track 311 a in the examples of FIGS.57A-E), at the same time the target region receives a concentrated doseas in target 318, the moving beam path reaching an effective focus onthe target region.

In general, where a stereotactic beam pattern is described herein as“one or more beams”, “a plurality of beams”, or “at least one beam”,these expressions include treatment configurations in which a collimatedbeam is moved continuously or incrementally over a selected stereotacticposition range during radiation emission so as to achieve an equivalenttreatment goal having a focused or concentrated target radiation dose.

Beam axis 1400 (or for multiple beams, each of axes 1400 a-c) may beselected to follow a tissue path which avoid vulnerable structures ortissues which are remote from target 318, so as to minimize dosagereceived by such tissues. For example, in treatment of the macula formacular degeneration, axes 1400 a-c may be selected to deliver aselected dose of beam treatment (e.g., a selected dosage of absorbedX-ray energy) to a target 318 on or near the retina 340, centered on themacula 342 while minimizing absorbed radiation by the optic nerve 350,the lens, and the like. In the example shown, three beam axis 1400 a,1400 b and 1400 c are defined, so that the beams directed towards theposterior eye enter the body on the surface of the anterior sclera 17 atpoints 311 a, 311 b and 311 c, each entry point a selected distancebeyond the limbus 26. Such beam orientation can avoid or minimizeabsorption by the lens and other structures within the eye, byappropriate selection of the beam paths.

As illustrated in FIG. 30A one or more of beam axes (1400 a, 1400 b and1400 c) are defined such that each axis lies within a conical conceptualsurface and whereby each beam intersects the apex of the cone. The conemay be defined having as its conical axis the treatment axis 19 with theapex disposed at target 318. In this example, treatment axis 19 isdefined parallel to reference axis 18, having x-y offsets define in anperpendicular plane by “dx” and “dy” respectively (for a treatmenttarget intersected by the reference axis the offsets are zero). Once thetreatment axis 19 is defined, the base 34, the apex angle (“Φ” in FIG.7), and rotational positions of axes 1400 a-c with respect to axis 19,may be adjusted to provide both beam intersection at about target 318 aswell as to provide entry points 311 a-c located at a desired position ofthe body surface.

In one example of an orthovoltage X-ray treatment for maculardegeneration, offsets dx and dy are selected to define a treatment axis19 centered on the macula, angle Φ is selected to provide intersectionof beams 1400 a-c on the macular surface, and base 34 is selected toprovide surface entry points 311 a-c in a region of the lower anteriorsclera beyond the boundary of limbus 26. In this example, an X-ray beamsource may positioned by positioning device (see 115 in FIGS. 33 and 37so as to project a collimated beam from a selected X-ray source distanceso as to form a beam having a characteristic width at tissue entry “w”.Note that although a treatment beam may be projected through an eye-lidor other tissue proximal to the eye, the eyelids (in this case the lowereyelid) may be conveniently retracted so as to expose an additional areaof the anterior sclera 17.

Note that in the most general case, treatment axis 19 need not beparallel to reference axis 18, and target 318 may be located relative toaxis 18 by other analytical methods not including a separately-definedtreatment axis. On the other hand, a real or at least conceptual hazardof high degree-of-freedom robotic systems employing energy beamtreatment, is the large possible range of beam paths (e.g., upon acontrol system failure), and associated risk issues, regulatorycomplexity, and high end-user installation and site modification costs.

FIG. 30B depicts results of a procedure in which three beams werefocused on the back of an phantom eye model using a robotic system, andrepresents a radio chromic film after bench top delivery of 100 keVoverlapping x-rays at a target site 3250. A radio surgical phantom modelwas used in which a model eye was placed in the eye socket. Film wasplaced on the back of the model eye and x-rays were delivered to atarget representing the macula. The region of overlapping x-ray beams3275 are shown at their overlap region where the dose is 24 Gy. Theoptic nerve 3260 is depicted lateral to the overlapping set of beams ata scaled distance from the center of the overlap. A rapid isodose falloff 3273, 3277 occurs lateral to the overlapping region 3275 and wellaway from the optic nerve 3260. Notably, the isodose depicted at region3265 is indeed between about 1% and about 10% of the dose (0.24 Gy-2.4Gy) at the treatment spot 3275. These data are a consequence of theoverlapping beam geometry as well as the fine beam collimation; they arephysical proof of the ability of finely collimated overlappingorthovoltage x-ray beams to create well-defined treatment regions. Dueto the 10-100 fold difference in treatment dose to optic nerve dose,fractionation is not required, and the entire dose can be given to thetreatment region in one session with minimal concern for injury toimportant structures, such as the optic nerve. These overlap regions canbe optimized and/or placed anywhere within the eye which is determinedby the treatment planning system and depends on the beam energies,collimation, and filtering. The degree of overlap is also to an extentdetermined by system parameters. For example, treatment of the entireregion of the retina for macular degeneration may be different than thatfor tumors or for hemangioma.

FIG. 30C-D are plots illustrating a stereotactic 3-beam dose map ofretinal dose measured by radiometry on a phantom eye or mannequin (byoptical density analysis of the exposed film), without eye motion, asdescribed herein. In this example, the beam trajectories aresubstantially as shown in FIG. 30A.

The contour dose map of FIG. 30C shows that the 4 mm target region liesentirely within the 80% isodose (20 Gy based on a maximum level of ˜25Gy). Indeed the area of the 24 Gy isodose (about 96%) is roughlyco-extensive with the 4 mm target region. The optic disk lies entirelybeyond the 1 Gy isodose, and thus receives substantially less that 4% ofthe maximum dose. Note that while the term “penumbra” is used hereinspecifically to refer to dose distribution from a single collimatedbeam, it is instructive to note the concept as applied to a stereotacticmultiple beam dose map, and an 80%-to-20% isodose cumulative “penumbra”is indicated in FIG. 30C and FIG. 30D as the span between the 20 Gyisodose and the 5 Gy isodose, based on a maximum combined dose level ofapproximately 25 Gy (note, dose levels may vary substantially dependingon treatment plan particulars).

FIG. 30D is a plot of the dose profile corresponding to the line B-B inFIG. 30C, which is a transect through the target center and the opticdisk center. This profile provides a clear illustration of the isodosefall-off in the “penumbra” region, decreasing rapidly to a low value atthe margin of the optic disk.

Measurement of Human Eyes for Radiation Delivery to Target

In embodiments of radiotherapy methods and devices having aspects of theinvention, the overall eye axial length (distance from cornea surface toretinal surface) and the beam tissue path length (the path length oftissue to be penetrated by the treatment beam in propagating fromsurface to target) are relevant to important of treatment parameters.For example, the tissue path length is relevant to (a) the selection ofX-ray input beam spectral characteristics (determination of tubepotential and filters, see FIGS. 10 to 12), and (b) for a given X-raytreatment beam, the tissue path length as the beam is actuallyadministered to a patient determines the dose rate at target in Gy/min(see pre-target absorption indicated in the eye model of FIG. 20).Similarly, the eye axial length and other eye geometry are relevant totracking motion of the retina during administration of treatment, as isdescribed further herein and in U.S. Application No. 61/093,092 filedAug. 29, 2008 and No. 61/076,128 filed Jun. 26, 2008; each of which isincorporated herein by reference.

Thus it may be seen that measuring and/predicting the tissue path lengthfor the patient permits accurate calculation of the rate at whichradiation is absorbed by target tissue. In certain radiotherapyembodiments, for a known dose rate based on tissue path length, theduration of beam emission is conveniently controlled (e.g., a timer toshut off power to tube) so as to administer a planned dose to the target(e.g., one third of total planned dose for a 3-beam stereotacticprocedure). For this purpose, a series of experiments were performed todetermine appropriate eye measurements to establish the depth of targeton the retina. A correlation model was established to show the relationof the path-length to axial length of the eye.

Using a 3D laser scanner, a device which can precisely map thecoordinates on a surface, a series of points in three dimensional spacewas derived from the surface of several cadaver eyes. FIG. 31A shows atypical example of the mapping results from this protocol, which permitsmapping the shape and contours of the cadaver eye to a high degree ofaccuracy. With this model derived from the surface of cadaver eyes, theaxial length and path length can be measured directly. The axial length(AL) and path length (L3) are indicated, the beam path correspondingapproximately to the beam path shown in FIGS. 18 and 20, directedthrough the sclera entry spot 311 to the target center 318 (e.g., maculaor fovea), the beam entering the eye beyond the limbus of cornea 35 ofeye 30.

As shown in FIG. 31B, the tissue path length and axial length can thenbe correlated or related to one another. In the initial dataset, thiscorrelation has been determined to be fairly linear, which depicts aseries of seven cadaver eyes. The relationship can be conveniently andusefully approximated by a variety of linear or non-linear equations orcurve fits. A simple example expressing the data is a linear curve ofthe form Y=aX+b, where Y=tissue path length (PL), and X=axial length(AL). For example where a=1 and b=−3, the equation is PL=AL−3, expressin millimeters. Alternative expressions may be used, and additional data(or more specialized data sets) may also be analyzed by the methodsshown. Alternative equations can be used to characterize the same data(e.g., PL=0.49*AL+9.7) without departing from the spirit of theinventions.

An A-scan is an ultrasonic measurement conventionally used inophthalmology where eye geometry is relevant, such as in refractivevision correction. It has be found by inventors herein that A-scanmeasured axial length can usefully be performed on the example cadavereyes and compared with Axial lengths determined from the laser scannerdata.

As shown in FIG. 31B, which depicts the measurements on a series ofseven cadaver eyes, the tissue path length (PL) and axial length (AL)can then be correlated or related to one another. In living patients andstudy populations, axial length may be obtained by an A-scan. An A-scanis an ultrasonic measurement conventionally used in ophthalmology whereeye geometry is relevant, such as in refractive vision correction. Ithas be found by inventors herein that A-scan measured axial length canusefully be performed on the example cadaver eyes and compared withAxial lengths determined from the laser scanner data. In general, thisrelationship can be conveniently and usefully approximated by a varietyof linear or non-linear equations or curve fits where tissue path lengthis a function of axial length, or PL=f(AL). In this example dataset,this correlation can be represented effectively as a linear function.This may be an equation of the form Y=aX+b, where Y=tissue path length(PL), and X=axial length (AL). An example where a=1 and b=−3, theequation is PL=AL−3, expressed in millimeters (curve 200 a in FIG. 31B).

It should be understood that different equations may be used aseffective mathematical representations of this data or similar data(e.g., PL=AL/2+9.5) without departing from the spirit of the inventions.Likewise, this or similar data may be expressed as a non-linearfunction, such as a quadratic equation or the like (curve 200 b in FIG.31B). Alternative expressions may be used, and additional data (or morespecialized data sets) may also be analyzed by the methods shown. Forexample, such ocular data may be represented by alternative non-linearfunctions, or may be embodied or carried out by look-up tableinterpolations rather than function evaluations, and the like.Additionally, anatomic data sets correlating additional patientattributes (age, gender, or the like), may be assembled, and predictiverelationships obtained relevant to these patient populations.Mathematical relationships representing this data may be including inthe software of radiotherapy system 10, and used to predict treatmenttissue path length, based on physician measurements and inputs for aparticular patient.

In certain alternative embodiments, the functional relationship fortissue path length may be based on more than one anatomic measurement,other measureable patient characteristics (e.g., refractive data), orother patient history data (age, gender, and the like). Advantageouslyand more generally, the method illustrated in the above example may beextended to other radiotherapy procedures in addition to its use inocular treatments for to the macula. One embodiment of the method may besummarized as comprising the steps:

(a) selecting one or more input parameters (anatomical measurements,other human measurements and/or other patient-specific characteristicssuch as age, gender, and the like), such as P₁, P₂ . . . P_(i);

(b) characterizing variation in a relevant patient population withrespect to the selected parameters (e.g., studies of anatomical or othermeasurement variation in patient populations, optionally as a functionof other patient-specific characteristics);

(c) correlating the population variation with the treatment tissue pathlength PL for a radiotherapy treatment plan;

(d) determining a mathematical function and/or calculation algorithmeffectively expressing a relationship between the selected parametersand the tissue path length, which may have the form PL=f (P₁, P₂ . . .P_(i));

(e) determining data for the selected parameters for a specific patientto be treated;

(f) using the mathematical function and/or calculation algorithm todetermine PL for specific patient to be treated (PL₀);

(g) modifying or adjusting one or more parameters of the radiotherapytreatment plan based on the value of PL₀. (e.g., beam duration or dose,spectral energy, filtration, collimation geometry, beam orientation, orthe like); and

(h) treating the patient according to the modified or adjusted treatmentplan

Method embodiments such as the above example may be integrated intoradiotherapy treatment devices having aspects of the invention, such asby including effectuating software code in computerprocessor-controllers of a radiotherapy system, so as to enable thetreatment device to carry out one or more of the steps of the method.

In FIG. 31C, for each of seven example cadaver eyes, the A-scan derivedaxial length is shown, together with the laser-scanner value of tissuepath length, and a calculated tissue path length according to theexample linear formula (PL=AL−3). For clarity of presentation, the sevenexample eyes are ordered by increasing A-scan axial length. It can besee that with minimal scatter, the results of the A-scan are a goodpredictor of path length. The maximum error introduced by the A-scan inthese data is approximately 0.3 mm. It has been shown by inventorsherein that an error of 1 mm in path length would introduceapproximately 3% error into the dose calculation for absorption at aretinal target. Therefore, an error of 0.30 mm introduces approximately1% error in dose, which quite small and clinically acceptable. Based onthis discovery, a method embodiment having aspects of the inventioncomprises determination a patient's eye axial length by means of apre-operative A-scan, and then predicting the tissue path length of atreatment beam, and adjusting at least one treatment parameter based onthe tissue path length (e.g., beam duration time).

FIG. 31D is a plot depicting the relation between measured patientanatomy and tissue path length for an exemplary radiotherapy treatmentplan including X-ray beam paths such as are described in FIGS. 13-20 and29. In the particular example shown, these include narrowly collimatedbeams entering the eye at the pars plana (see beams b1-b3 in FIG. 17 andbeams 1400 a-c in FIG. 30A), and propagating to a macular targetapproximately centered on the fovea (see FIG. 19A).

The graph in FIG. 31D below depicts the correlation between the axiallength (AL) as compared to the path length (PL) through which the X-raytravels. Data such as shown in FIG. 31 may be included in treatmentplanning methods and devices, such as in software as a computationalformula (e.g., the formula PL (mm)=AL (mm)−3), look-up table, or thelike. A patient-specific anatomic measurement 280, such as an ultrasoundA-scan axial length (e.g., 23.5 mm) may then be used (e.g., input to apatient-specific system configuration file accessed by a computerprocessor) to determine a treatment path length 281 (e.g., 20.5 mm). Thetissue path length effects the propagation of X-ray energy to thetreatment target as photons are absorbed in the tissue (see FIGS. 12 and20).

The tissue path length determined as depicted in FIG. 31 may be used intreatment planning methods and devices to regulate the applied X-rayintensity and/or duration so as to achieve a planned target dosage.Conveniently, the duration of X-ray beam emission may be timed andcontrolled to account for variation in patient specific tissue pathlengths. FIG. 32 is a plot depicting the relation between the beamtissue path length and the duration of beam emission required to delivera planned target dose for an exemplary embodiment of a X-ray treatmentsystem having aspects of the invention. In this example, the target doseis about 8 Gy delivered to the macula. A patient-specific tissue pathlength 290 (e.g., 20.5 mm) may then be used to determine a beam duration291 (e.g., 119 sec), such as be software implementation in a systemprocessor/controller.

Radiotherapy System Embodiments—Overview

FIG. 33 is a perspective view of an exemplary embodiment of an X-raytreatment system 10 having aspects of the invention, for treating oculardiseases. The system is shown with a phantom of a patient's head engagedwith head-chin restraint device 160, the head aligned in treatmentposition. System 10 includes a radiotherapy beam generation module, forexample comprising one or more X-ray tubes 112, each having a collimator118 for producing a tightly collimated X-ray treatment beam. The system10 includes a radiotherapy control module or subsystem (not shown) whichpreferably includes an interface display, processing module, a powersupply. The system includes an imaging module 400, which can include oneor more cameras and associated light sources, such as LEDs orlow-powered lasers.

FIG. 33A is a perspective view of an exemplary embodiment having aspectsof the invention of an X-ray treatment system 10 for treating oculardiseases. FIG. 33B is a plan view of the treatment system embodiment ofFIG. 33A, further showing associated system processors 501 and operatorinput/output devices 502-503, depicted as installed in an exemplaryoperating console 500. FIGS. 34-40 illustrate alternative or additionalaspects of system 10.

With reference to FIG. 33A, the system is shown with a phantom of apatient's head engaged with head-chin restraint device 160 and headfastening 161, the head aligned in treatment position. System 10includes a radiotherapy generation module or X-ray source assembly 420,for example comprising one or more X-ray tubes 112, each having acollimator for producing a tightly collimated X-ray treatment beam. Thesystem 10 includes a radiotherapy control module which preferablyincludes an interface display 502, processing module 501, operator inputdevices 503 and a power supply (not shown). The system includes animaging module 400, which can include one or more cameras and associatedlight sources, such as LEDs or low-powered lasers.

In the embodiment shown, system 10 includes an automated positioningsystem (APS) 115 for moving and aiming the X-ray source assembly 420(including X-ray tube 112 and collimator 118) to direct a treatment beamto a target from one or more selected directions. The system 10 furtherincludes eye-guide, eye alignment and stabilizing module 625. Furtherdescription of system 10 follows below.

FIG. 33B illustrates one particular embodiment of an operating consol500 having aspects of the invention, suited to house the components ofsystem 10 and to provide for its effective and safe operation in patienttreatment. It should be understood that the intercommunicatingcomponents of system 10 can be mounted in a variety of differentarchitectural configurations, and the components may be distributedremotely and/or integrated with other devices without departing fromspirit of the invention. For example, components shown in FIG. 1B in a“desktop” type mounting (e.g., X-ray source positioning system 115) mayalternatively be supported in a ceiling or wall-mount configuration, ormay be mounted on wheeled carts, or the like. Similarly, alternativeembodiments of system 10 having aspects of the invention may beoptimized to reduce size, weight and volume to permit integration ofcomponents into one (or a few) physical modules, for integration intoother medical systems, and/or to provide portability.

The exemplary operating consol 500 provides seating 506, 507 for patientand one or more operators, and may also include supplemental radiationshielding 508 a,b between the operator and X-ray source assembly 420.Cameras of imaging system 410 (e.g., one or more CCD or other electronicimage capture devices) communicate with computer processors 501 ofsystem 10. Processors 501 communicate with operator displays 502 andoperator input devices, such as keyboard 503. The console also housesone or more computer processors 501, operator input/output/displaydevices 502 a-503 a, and interconnections 505 to various systemcomponents, such as imaging system 420, positioning system 115 and X-raysource assembly 420.

In should be understood that computer processor elements, and associatedinput, output, display, memory and/or control components can bedistributed, embedded and/or linked in a number of alternativearrangements by means known in the electronic arts, and the arrangementshown in FIG. 33B is exemplary. Likewise, intercommunication ofelectronic elements of system 10 may be wireless, and alternativelycertain processor, memory and/or I/O functions may be performed remotelyor over a network.

For example, supplemental displays and control devices communicatingwith processor 501 can be positioned to assist or interact with anoperator or physician while working close to the patient (e.g., prior toX-ray beam emission). An auxiliary display/input device 402 b-403 b isshown to adjacent to eye-guide positioner 600, e.g., to assist anoperator in engaging and aligning an eye-guide (110 in FIG. 40) on apatient's eye, and/or in adjusting the positioner 115 and X-ray source420 to an initial treatment position.

In addition, a number of sensor elements may be embedded in thecomponents of system 10 in communication with processor 501 of providefeedback, monitoring and safety functions. For example, chin-headrestraint assembly 160 may include a right-left pair of hand grips 163for the patient to hold, helping to maintain the patient's torso andshoulders in perpendicular alignment to eye-guide 110. The hand gripsmay include force or contact sensor to monitor that the patient is inposition. Similar sensors may be included in head-fastening 161, e.g.,to monitor head position and/or motion. Such safety/monitoring sensorsmay produce trigger signals to alert an operator and/or may be employedto gate or interrupt X-ray emission during treatment. In anotherexample, light intensity and/or spectral sensors (not shown) may bepositioned on system 10, and configured to automatically control thelighting elements of imaging system 400 (e.g., lights 405,406) so as tomaximize image recognition performance as well as other operatingparameters.

The console 500 comprises a power/accessories assembly 509 which mayinclude power supply, power regulators, high voltage source and/or otheraccessories needed for operation of X-ray tube 112. It should be notedthat a number of alternative commercially-available types of X-ray tubesor sources (as well as dedicated tube designs) may be included in X-raysource assembly 420 without departing from the spirit of the invention.An X-ray power supply/high voltage source may be a relatively large unitwhich is most conveniently housed separately from movable X-ray sourceassembly 420. In the example shown, conduits 425 lead from X-raypower/accessories assembly 509 in console 500 via guide spool 426 toconnect to X-ray tube 112. The guide spool 426 is configured to supportconduits 425 as X-ray source assembly 420 moves during system operation,as is described further herein.

Additionally, many commercially-available X-ray tubes are designed touse liquid cooling to increase output capacity. Power supply/accessoriesassembly 509 and conduits 425 may optionally include connections tocoolant and/or an integrated coolant supply/chiller, so as to supplycoolant to X-ray tube 112. Optionally, assembly 509 may includebatteries or an uninterruptible power supply (UPS), e.g. of sufficientcapacity to permit system 10 to complete a radiotherapy treatmentnotwithstanding a loss of line power during the treatment.

The exemplary operating consol 500 provides seating 506, 507 for patientand one or more operators. System 10 may be configured to minimize strayX-ray radiation. However, as a radiation safety practice, console 500may include supplemental radiation shielding 508 a between the operatorseating position 507 and the X-ray source assembly 420. The shieldingmay optionally include a radio-opaque window 508 b (e.g., comprising atransparent silicate glass including heavy nuclei such as lead) topermit direct observation of (and reassurance to) the patient duringX-ray emission. Such an operator station configuration allows closemonitoring of the patient during irradiation treatment, and promoteseasy access for direct assistance to the patient when radiation is notbeing emitted. Alternatively or additionally, observation cameras (notshown) may be mounted so as to allow an operator and/or physician tomonitor the patient during treatment via electronic displays.

X-Ray Source and Positioning System

FIGS. 34-36 depict the X-ray source and collimator (112 and 118 in FIG.33) having aspects of the invention, shown in FIG. 3 as aligned inposition for treatment of the retina of an eye. FIG. 34 shows apatient's head including cross-section of an eye in the vertical planeof symmetry of the eye, shown in association with imaging system 410,and an X-ray source assembly comprising X-ray tube 112 and collimator118. FIG. 35 is a perspective detail view of the system components shownin FIG. 34 together with portions of the positioning system 115 (seeFIG. 37), illustrated in association with a phantom patient eye 30coupled to eye-guide 110. FIG. 36 is a longitudinal cross-sectional viewof collimator 118 and a portion of X-ray tube 112. FIG. 37 is aperspective illustration of an embodiment of a positioning system 115having aspects of the invention, in this example a 5-degree of freedomautomated positioning assembly, shown supporting X-ray tube 112 andcollimator 118 in association with a phantom eye 30. FIG. 38 depictsembodiments of a motion control system in which the collimator 118.

As shown in FIGS. 34 and 35, the X-ray source assembly 420 is aligned inposition for treatment of the retina target 318 of an eye 30. Forclarity and simplicity of illustration, the example of FIGS. 34-35 showsthe assembly 420 aligned in the vertical plane including treatment axis2820 with an upwardly directed X-ray beam axis 1400. This corresponds toexample beam 2 (b2) as shown in FIGS. 15 and 17, such that the value ofazimuth angle θ is 180 degrees. The polar angle (angle between treatmentaxis 2820 and beam axis 1400) is shown as approximately 30 degrees. Itshould be understood that orientation of beam 1400 may be selected andadjusted to suit a particular treatment plan method having aspects ofthe invention, and need not be restricted to any of the orientationsshown in these examples.

FIG. 34 shows components of imaging/data acquisition system 410including data acquisition devices functioning to track and/or identifythe position of the eye 30, its anatomical structures (e.g., the limbusof the eye), and/or an eye-guide 110. In the example shown, the dataacquisition devices comprise one or more cameras (e.g., camera 401located aligned with the eye geometric axis 2810, camera 402 aligned offaxis, or both). The cameras may be sensitive to visible and/ornon-visible wave lengths (e.g., IR) and may include filters configuredto tune sensitivity to certain ranges of wavelength. Alternatively oradditionally, the data acquisition devices may comprise non-lightemitters and detectors, such as ultrasound transducers/generators,radio-frequency devices and the like. A number of types of fiducials,transponders and/or mirrors may be included as system components toenhance the function of the data acquisition system. Likewise, radiationemitters may be included, such as lights, lasers, LEDs and the like.

In certain exemplary embodiments described herein in detail, the imagingsystem 410 comprises an off-axis camera configured to measure theeye-guide 110 and eye position relative to the Z axis, optionallyassisted by one or more lights 406 (e.g., visible or IR LEDs). Anon-axis camera 401 is included, configured to determine the alignment oroffset of the eye 30 and/or eyeguide 110 with axis 2810. Similarly, oneor more lights 405 (e.g., LEDs) may be included to assist camera 401.

In certain embodiments described in detail herein, eye-guide 110includes an axially perpendicular mirror (not shown in FIG. 34), andimaging system 410 includes a axial collimated light pointer 403 (e.g.,including a diode laser, beam splitter, and camera filter) aligned toreflect off the mirror to be received by camera 401, permittingdetermination of the axial alignment (or alignment difference) ofeye-guide 110 with respect to axis 2810.

In alternative embodiments described in detail herein, eye-guide 110includes a geometric pattern of highly-reflective fiducials, and camera401 is configured to image the pattern, the camera in communication witha system processor unit programmed to determine the alignment (oralignment difference of eye-guide 110 with respect to axis 2810.

The collimator 118 is positioned close to the eye of the patient, so asto allow for an acceptable penumbra as well as a tightly collimatedradiation beam as described in the above noted U.S. application Ser. No.12/103,534 filed Apr. 15, 2008; Ser. No. 12/027,069 filed Feb. 1, 2008;and Ser. No. 12/100,398 filed Apr. 9, 2008; each of which isincorporated by reference. In certain embodiments, the collimator exitaperture diameter is between about 1 mm and about 4 mm so that the spotsize on the back of the retina is approximately about 2 mm to about 7mm.

FIG. 36 depicts a cross-section schematic view of a portion of an X-raysource assembly 420 of system 10. Laser pointer 1410 travels through abeam splitter 1220 and exits the collimator with its center aligned withthe radiation beam. In the example shown, the x-ray anode 1420 has agreatest dimension between about 0.1 mm and about 5 mm and can be placedat a distance L from the retina of about 50 mm to about 250 mm, andpreferably from about 100-200 mm, and more preferably about 150 mm.Maintaining the anode 1420 at such a distance from the retina in oneembodiment allows maintaining a low penumbra. The radiation beam 1400 isdelivered through the collimator 118, and its diverging path enters theeye approximately in the pars plana region, missing the importantstructures of the anterior chamber such as the lens and the cornea. Inthe example shown, eye-guide 110 lens contacts the sclera and/or thecornea of the eye.

As shown in FIGS. 34 and 36, the collimator 1405 is preferably collinearwith the light source 1450, which can act as a pointer to indicate thepoint on the eye through which the radiation enters the eye 1300. Insome embodiments, the light pointer position is used to track theradiotherapy source vis-à-vis an image recognition system whichidentifies the position of the pointer relative to an ocular structure(e.g., the limbus) and the radiotherapy device is then moved based onthe image (e.g., to a region further away from or closer to the limbusof the eye). In some embodiments, the physician visualizes the positionof the laser pointer relative to the limbus and manually adjusts thex-ray source into position.

Light pointer 1410 (e.g., a laser beam emitted from a source 1450) iscoupled to a collimator 1405, or behind the collimator 1405, so that thelight pointer 1410 is coincident with an x-ray beam 1400; the lightpointer 1410 can indicate the position 311 on a surface of an eyethrough which the radiation source enters by tracking angles ofincidence of the collimator and x-ray beam. Cameras of imaging module400 (see FIG. 33A) can track point 311 and image processors can be usedto confirm this position to a user, or to trigger automated controls, ifposition 311 should be out of a threshold of accuracy, per a treatmentplan.

As illustrated in FIG. 34, for convenience certain dimensions relevantto beam collimation and treatment anatomy may be identified as L0, L1,L2 and L3, where:

L0 is the total distance from the X-ray source anode 1420 to a treatmenttarget 318 (e.g., macula or fovea);

L1 is the distance from the X-ray source anode 1420 to the collimatorexit aperture plane 1405;

L2 is the distance from the collimator exit aperture plane 1405 to thetissue surface beam spot 311 (e.g., sclera surface at or near parsplana); and

L3 is the length of the propagation path of the X-ray beam within tissueto reach the treatment target, the distance from beam tissue entry spot311 to the treatment target 318.

In an exemplary ocular treatment plan having aspects of the invention,the collimator exit plane 1405 is typically within a distance L2 ofabout 1 cm to about 12 cm from the beam entry point 311 on the sclera.However, in alternative embodiments, the collimator may be configured tobe in contact with the surface of the eye or adjacent face, and mayinclude a suitable resilient or cushioning biocompatible contactsurface. The distance D may be selected as a trade-off between the goalof minimizing penumbra of beam 1400 at the retina, and in avoidinginterference and discomfort of the patent, e.g., due to spacelimitations when working close to the face. In certain embodiments, ahigh degree-of-freedom (DOF), high range-of-motion robotic positionermay be employed to position X-ray tube 112 and collimator 118, which canbe programmed and/or controlled to maneuver so as to avoid interferencewith objects and parts of the patients body. See for example, highdegree-of-freedom robotic surgical control systems such as employed inthe CyberKnife® robotic radiosurgery system (Accuray, Inc. Sunnyvale,Calif.) and the da Vinci® minimally-invasive surgical system (IntuitiveSurgical, Inc., Sunnyvale, Calif.). However, the da Vinci is notautonomous and requires an expert surgeon to move its arms. TheCyberknife is in fact autonomous. However, the linear accelerator whichmoves around the patient is over 1 ton in weight and cannot move closeenough to the patient to deliver beams of X-ray to the eye. Furthermore,the system does not include an eye stabilization system to allow foralignment relative to the eye.

However, alternatively and advantageously, a limited range-of-motionpositioner (see 115 in FIG. 33) may provide greater precision andaccuracy of radiotherapy, particularly where a single DOF is moved tostereotactically re-position the X-ray source 112 for sequential beamtreatment applications, e.g., by minimizing positioning error, vibrationand dynamic effects. In addition, a real or at least conceptual hazardof high degree-of-freedom robotic systems employing energy beamtreatment, is the large possible range of beam paths (e.g., upon acontrol system failure), and associated risk issues, regulatorycomplexity, and high end-user installation and site modification costs.

In one example, L2 is selected to be about 55 mm and L0 is selected tobe about 150 mm, suitable for use with APS 115 shown in FIG. 33 anddescribed further in FIGS. 37-38. See, for example, embodimentsdescribed in the above noted U.S. application Ser. No. 12/100,398 filedApr. 9, 2008; which is incorporated by reference.

In many embodiments, only a small amount of movement is required of thex-ray source 112 to treat a disease of the retina, such as maculardegeneration and/or diabetic macular edema. In these embodiments, sixdegrees of freedom can be applied to the x-ray source 110, but the rangeof each degree of freedom is may be limited. Because each treatment doseis relatively short and applied over a small distance, the robot cansacrifice speed and travel distance for smaller size.

Alternatively, multiple X-ray sources 420 may be employed, e.g., havinga fixed relationship to each other, to supply multiple stereotacticbeams for treatment. However, embodiments employing an APS such as shownin FIGS. 33-38 can be more compact, lighter, and less expensive, andavoid the space limitations of excessive equipment working close to theface.

FIGS. 37 and 38 depict embodiments of a constrained X-ray positioningsystem to treat the eye (e.g., as included in APS 115). Positioningsystem 115 is depicted. Translation in the X-Y-Z motion is shown and inangular orientations Φ and θ. This positioning system is customized forclose treatment and to treat the eye. The range of motion along eachdegree of freedom is limited and the positioning system 155 deliversx-rays to the eye. X-ray source 112 is positionable with respect to theeye, which can be tracked, in some embodiments, with a contact member110 and module 625.

Note that imaging support 412 (see also FIG. 35) is shown in thisexample projecting from XYZ stage 416, so that imaging system (410 inFIG. 35) may be supported independently of the Φ and θ actuators 413 and414 respectively, but may be positioned by XYZ stage 416 so as to be inalignment with the eye geometric axis 2810 or treatment axis 2820, forexample. However, it should be noted that all or portions of imagingsystem 410 may be supported either together with or independently of anyof the degrees of freedom of positioning system 115, without departingfrom the spirit of the invention. For example, one component of imagingsystem 410 (e.g., a camera) may be mounted directly to tube 112, whileother components are mounted to XYZ stage 116, and yet other componentsare mounted and positioned independently of all of the 5 DOF of theexemplary positioning system 115, e.g., by an independently actuated andcontrolled robotic support, or the like.

FIG. 38 depicts embodiments of a motion control system in which thecollimator 118 is moved by the positioning system around the tip of acone with the x-rays converging on a focal spot within the eye, such asthe macula. The distance along the center of the cone to the collimatoris constant for a given angle Φ which refers to the angle the collimator118 makes with treatment axis 2820. The distance from the edge of thecollimator to the focal spot is constant for any Φ or θ. Because themotion system is rigidly constrained around an axis, the error is verysmall in terms of positioning and movement. In some embodiments, thedistance from the X-ray source anode 1420 to the retinal target can befrom about 200 mm to about 100 mm, and in an embodiment described indetail herein, this distance L0 may be about 150 mm. Angle Φ can changedepending on the distance prescribed or desired. In some embodiments,the angle Φ is variable and can be changed depending on the desiredentry position of the beam into the eye. Nonetheless, to achieve thedesired motion around the point of focus, the collimator moves aroundthe rim of a cylinder such that the collimator can emit radiation frompoints at a constant angle with respect to the target. Such movementenables the positioning system to accurately position the collimator andx-rays tube along an arc. This single degree of freedom afterpositioning makes the therapy efficient and precise.

In the exemplary embodiment of positioning system 115 shown in FIG. 37,the system comprises a base (421 in FIG. 33A). Note that the base 421 isshown as a table-mount type base, but may be alternatively supported byother mounting structures known for medical devices, such as overheadmountings, cantilevered wall mountings, wheeled cart mounting,retractable or folding mountings, or the like.

In this example, base 421 supports a proximal XYZ stage 116 having threesequentially-supporting mutually-perpendicular linear actuators, whichin turn supports a more distal rotational θ actuator 414 which has anaxis of rotation parallel to the Z axis, which in turn supports a stillmore distal rotational Φ actuator which adjusts the polar angle relativeto the Z axis. The most distal X-ray source assembly 420 is supported bythe Φ actuator. This exemplary positioning arrangement shown may beoperated in a number of alternative modes. However, it is particularlywell suited to a stereotactic mode of operation wherein the X, Y, Z andΦ degrees of freedom are adjusted and fixed relative to treatment axis2820 and target 318, and subsequently X-ray source assembly 420 isre-positioned by motion of the θ actuator 414 to successive beamtreatment positions, as shown in FIG. 38. Alternative embodiments ofpositioning system 115 for the X-ray source assembly 420 having aspectsof the invention have differing proximal-to-distal ordering of thedegrees of freedom shown, and may have greater or fewer than 5 degreesof freedom.

Eye Alignment, Stabilization and/or Tracking

FIG. 39 illustrates a top view of one embodiment of a system 625 forcontrollably positioning and/or stabilizing the eye of a subject fortherapeutic treatment. The upper portion of FIG. 39 shows a blockdiagram of a system 100 for carrying out a method having aspects of theinvention. The lower portion of FIG. 39 shows an eye-guide module topermit alignment, stabilization and/or tracking of an eye prior to andduring treatment.

In the illustrated embodiment, system 100 includes one or more cameras102 positioned to image eye 10 along the geometric axis 810 (or 2810).Camera 102 provides video image data of eye 10 to a processor 106 andpreferably to a display 104. Coupled to display 104 is an imagegenerator/processor 106, such as a personal computer programmed withcommercially-available computer aided design software, capable ofgenerating and overlaying geometric images onto the image of eye 10appearing on display 104, and preferably configured to perform imagerecognition algorithms using eye images. Processor 106 may also includepatent specific data and images obtained prior to operation of system100, e.g., to include in displayed images, and/or to be used to providepatient specific geometry for treatment.

Eye-contact device 110 may be equipped with a plurality of positionindicators that are capable, in combination with detectors located inthe external coordinate system, to locate the position of the contactdevice in the external coordinate system. This type of tool-trackingsystem, has been described for use in image guided surgery, where it isnecessary to place a movable surgical tool, and typically also pre-oppatient images, in a common surgical frame of reference containing thepatient. In the present application, the position indicators may bethree or more beam-directing elements designed to reflect externalpositioning beams, e.g., microwave beams from known-position beamsources to known-position beam detectors, with the position of thecontact device being determined by a processor operatively linked to thebeam detectors. Alternatively, the beam-directing elements in theeye-contact device can be equipped with a plurality of LEDs mounted onthe device for directing, for example, a plurality of beams atknown-position detectors to determine the position coordinates of thecontact device in the external coordinate system. Such tool registrationsystems have been described, for example, in U.S. Pat. Nos. 7,139,601,7,302,288, and 7,314,430, all of which are incorporated herein byreference in their entirety.

In a third general embodiment the position-determining means takes theform of a collimated light-beam assembly, including a laser light sourceand one or more optical components, such as a half-silvered mirror, foraligning the laser beam with the collimated irradiation beam produced bybeam source 108; such that the two beams are essentially coincident,along the same axis 810. In this embodiment, the beam-positioningassembly is moved with respect to the patient's eye until the laser beamis aimed directly onto the selected target region of the patient's eye,e.g., the macula region at the central rear portion of the retina. Ascan be appreciated, this will place the selected target region of theeye in registry with the therapeutic irradiation-beam; that is, thelaser beam acts as a reference beam that functions to place the eye inthe same frame of reference (coordinate system) as the irradiation beam.

More generally, the spatial registration and guidance of the contactdevice 110 may be through optical or electromagnetic sensor detection.In general, cameras or other detectors are mounted either on the system,or optionally in the treatment room, and are used to track and registerthe position of the eye or contact device 110. Cameras or detectors arethen able to determine and record the three dimensional position of thecontact device 110 in real time, and therefore the position of the eyeas it is positioned. A calibration process can be used to determine therelative spatial position of the contact device to a known referenceframe, as well as in combination with optional images. The calibrationinformation can be stored in a reference file on the computer and usedby a software program.

System 100 also may includes a processor or control unit which has agraphical user interface for receiving instructions from, and presentinginformation such as alignment and system functionality data to, a systemoperator. Further, the control unit may be in electronic communicationwith one or more of the other components of system 100 described above,e.g., the motors controlling the beam-positioning assembly, the motorscontrolling the eye-positioning assembly, and sensors, detectors andbeam sources for determining the position of the eye-contact device inthe external coordinate system, as described above.

FIGS. 40A-B illustrate perspective views of an exemplary embodiment 625having aspects of the invention of a contact device or eye-guide and eyealignment and stabilizing module configured for use with system 10 (itadditionally may be usefully employed independent of system 10). Thismay be used together with head-chin restraint device 160, which includesa head support or support 170 for stabilizing the head of subject, andincludes a chin rest 172.

FIGS. 40A-B and 41A-B depict one example embodiment of an method ofaligning and/or stabilizing a patients eye 30 and engaged eye-guide 110with the coordinates of radiotherapy system 10, using a laser beacon 150a mechanism by which the contact device 110 can be used to align the eyewith laser alignment system 800, including laser device 150 (alternativeimage-based alignment subsystems are described herein). Optionally, thealignment mechanism also directly aligns a treatment system, such as aradiotherapy system (not shown in FIG. 40) in which the radiotherapysystem directs its energy toward the eye in relation to the alignmentsystem. Laser pointer beam 810 (which is collinear with the therapeuticbeam in some embodiments) is emitted from laser system 800 through acollimator opening 820 and reflects off the surface of beam-directingmirror 230 of the contact device 110. In the non-alignment case depictedin FIG. 40A, the laser pointer beam 810 will not reflect off the surfaceof mirror 230 collinearly with the collimator opening 820, but will beoff-axis, as shown by reflection beam 830. The orientation of the lasersystem 800 and/or the contact device 600 can be manually orautomatically adjusted by direct visualization of the location of thereflection beam 830 or by sensors that detect the location of thereflection beam 830 and adjust the laser system 800 to bring the laserreflection beam 830 into alignment. FIG. 40B shows a case where thelaser pointer is in fact aligned, the laser pointer beam 810 isreflected, and the laser reflection beam 830 is substantially collinearwith the laser pointer beam 830.

See description regarding FIGS. 54A-B regarding geometry of mirror 230and angular alignment of eye-guide 110. FIG. 34 depicts a laser beacon403 mounted to project coaxially with a system image detection camera401. The image processing and recognition methodology description hereinconcerned other embodiments for image based eye alignment with respectto FIGS. 34-35 and FIGS. 21A-E are applicable to detecting thedeflection of laser beacon 150 (403 in FIG. 3A) from mirror 230, andmeasuring any alignment error thereby. For further description oflaser-beacon alignment, reference is made to application Ser. No.12/027,083 filed Feb. 1, 2008; Ser. No. 12/027,094 filed Feb. 1, 2008;Ser. No. 12/027,069 filed Feb. 1, 2008, each of which is incorporated byreference.

Alternatively or additionally, alignment of eyeguide 110 with a systemcoordinate axis may be determined by image capture and recognitionmethods. See device and method embodiments described herein with respectto FIGS. 48, 50, 55 and 57, for example, and the sections captioned“Imaging subsystem” and “Example of image-based eye and eye-guidemeasurements.”.

The eye-positioning assembly 600 used to position the eye-contact oreye-guide device at a selected orientation. Contact device 110 may beattached to a control arm 180 in the positioning assembly 625, which isbeing fed into slot 610 of drive mechanism 600. In some embodiments, thecontact device 110 of the system can be attached to a coupling componentto hold the eye in place.

Eye-guide device 110 is preferably disposable such that a separate (e.g.disposable) contact device 110 is employed for each subject and/or use.Alternatively, contact device 110 may be non-disposable and be treated,e.g., with anti-infective agents, prior to being utilized in multiplesubjects' eyes. Drive mechanism 600 is fixed to base 620 throughconnector 640, which may robotically controlled or manually controlled,and has a known coordinate system. In one embodiment, drive mechanism600 is fixed in a known, or predetermined, location with respect to thehead positioning system (not shown) and/or the eye of the subject (notshown) and/or the positioning system of the radiotherapy device. Pushbutton 630 allows free manual positioning of contact device 110 intoand/or out of slot 610. The control arm 180 is fully engaged with thedrive mechanism 600 and is fixed in a known, or predetermined location,which allows the eye of the subject to be fixed in a known, orpredetermined location, when contact device 110 engages the eye.Although not shown, the eye-positioning device may include internalposition sensors operable to detect the position of the end of arm 110in the external coordinate system, in accordance with movement of thearm in any selected direction.

Note that the eye-guide support arm 180 is illustrated in the examplesshown as extending primarily in the “X” direction of the systemordinates. It should be understood that alternative embodiments ofmodule 625 may have the eye-guide 110 supporting from below or above inthe Y direction, or from the Z direction, or combinations of these.Eye-guide 110 and eye alignment and stabilizing module 625 is describedfurther with respect to FIG. 41 et seq.

Imaging Subsystem

FIGS. 34 and 35 illustrate a particular example of an imaging system 410having aspects of the invention. In operation, the imaging system 410may be configured for several functions, most of which may be performedautomatically using image processing and pattern recognition, including:

1. Alignment of eye 30 to eye-guide 110.

-   -   Monitor and assist in initial placement of the eye-guide lens        120 by physician (display and guidance).    -   Confirm alignment of eye-guide 110 (may be automatic).    -   Monitor and measure the relation of eye-guide lens 120 to the        patient's limbus 26, may be performed automatically using image        processing and pattern recognition (may be automatic).    -   Measurement and verification to identify the center of the lens        and the limbus in x-y (may be automatic).    -   Locate and measure the I-Guide in depth z (may be automatic).    -   Measure orientation of eye-Guide in angular space (may be        automatic).

2. Verification of entry position 311 of X-ray beam 1400.

-   -   Identify and calculate the position of the laser spot 1410        indicating scleral entry of the X-ray beam and relation to        limbus 26 (may be automatically performed, and may also be        operator-verified prior to X-ray emission).    -   The algorithm used may be based on imaging analysis of the        border of the limbus 26 as compared to the center of the limbus.        In one treatment plan example, the center of the X-ray beam is        placed about 4 mm from the limbus border, the beam diameter        being about 3.5 mm, so that the beam edge is about 2.25 mm        beyond the limbus (the beam 1400 traverses the pars plana region        to reach the target 318 at or near the fovea, and so minimizes        dosage to the lens.

3. Treatment monitoring (gating)

-   -   Continuous x-y-z-θ spatial monitoring of the eye-guide 110.    -   Continuous measurement of x-y limbus position (may be        automatic).

In the example shown in FIGS. 34 and 35, imaging system 410 comprisestwo cameras. The cameras may interface to computer processors (notshown) of system 10, e.g. via USB connectors. Illumination (e.g., LEDlights) may be controlled by signals from computer processors. Thecameras may include:

1 Main system X-Y camera 401 (on-axis)

-   -   Located along the center axis of the Automated Positioning        System (APS).    -   Will display live images to the physician at video rate (30 Hz).

2 Range Z camera (off-axis)

-   -   Mounted above the system axis.    -   Angled downward to obtain a perspective view of the fiducials        1-3 of eye-guide 110.

The lights 405, 406 and 407 may be configured provide safe, regulatedlight levels coordinated with imaging procedures, such that imagingapplications are insensitive to room light conditions. Regulation oflight level and/or wavelength spectrum (e.g., color specific or IR LEDs)may be automatic, such as 1 sensor feedback, and/or image processorfeedback, e.g., to account for ambient light, to maximize featurecontrast, process optimization and the like. Lighting functions mayinclude:

-   -   Lighting the field of view for the main system X-Y camera to see        the patient's eye.    -   Directing light along each camera path onto the retro-reflecting        fiducial targets for I-Guide monitoring    -   Lighting the lower limbus boundary 26 for enhancing the contract        for limbus detection.    -   Marking the X-ray entrance point with a laser spot that has been        aligned with the x-ray source.

Please see description below with respect to FIGS. 43A-E and the examplecaptioned “Example of image-based eye and eye-guide measurements” forfurther description of the methods of use of imaging system 410.

Eye Guide Systems

FIGS. 41A-B illustrate top views of an embodiment of a system forengaging the eye of a subject, the contact device 110 being reversiblyand controllably coupled to the cornea 200 and/or limbus and/or sclera239 of the eye 130 is schematically illustrated. The eye 130 includes acornea 200 and a lens 132 posterior to the cornea 200. The eye 130 alsoincludes a retina 134, which lines the interior of the rear surface ofthe eye 130. The retina 200 includes a highly sensitive region, known asthe macula, where signals are received and transmitted to the visualcenters of the brain via the optic nerve 136. The retina 200 alsoincludes a point with particularly high sensitivity known as the fovea.The eye 130 also includes a ring of pigmented tissue known as the iris138. The iris 138 includes smooth muscle for controlling and regulatingthe size of an opening in the iris 138, which is known as the pupil. Theeye 130 resides in an eye socket 140 in the skull and is able to rotatetherein about a center of rotation.

The eye-contact device 110 functions to stabilize the eye in a firstposition to provide interactive support (e.g. stabilization and/orcontrollable movement) for the eye while the eye is being treated. Thecontact device 110 includes a cup or eye-contact member 120 whichcontacts eye 130. The contact member 120 can be positioned on the eye ina variety of positions, and is therefore useful in a wide variety ofocular treatment procedures. In one embodiment, the eye-contact memberis in at least partial contact with the cornea 200. In the embodimentillustrated in FIG. 12B, the eye-contact member covers a substantialportion of the cornea (but does not necessarily touches the cornea). Themember 120 may also cover portions of the sclera. The contact member 120includes preferably a curved structure or “lens” that is substantiallycentered on the axis 235 and overlying the cornea 200.

The curved contact member 120 is preferably shaped with a concaveeye-contact surface that will substantially conform to the anteriorsurface of the cornea 200 of the eye 130. The contact surface of thecontact member 120 preferably has a radius of curvature that is greaterthan about 5 mm. In one embodiment of the invention, the radius ofcurvature of the inner surface of the eye-contact member 120 is 7.38 mm.Likewise, in a preferred embodiment, the radius of curvature of theouter surface of the eye-contact member 120 is preferably 7.38 mm. Itwill be appreciated that a 1:1 ratio of inner and outer curvaturesminimizes or eliminates refraction of energy through the eye-contactmember 120 in certain embodiments of the invention; in this embodiment,the contact member 120 is a simple cup for the eye 130. Alternatively,the inner and outer curvatures may differ to permit desired focusing ordiffraction of energy as it is transmitted through the eye-contactmember 120. In some embodiments, the contact member 120 is produced in avariety of shapes, one or more of which can be chosen for a givenpatient depending on his or her specific anatomy.

In one example embodiment, the eye-guide assembly 110 may comprise asterile, disposable cup or lens 120. Preferably, the eye-contact member120 can be fashioned from suitable material with attention tobiocompatibility, such as a number of materials well known in the art,such as poly(methylmethacrylate), or PMMA. Thermoset and/or thermoplastPMMA are contemplated by the present invention and are supplied by anumber of sources, such as Perspex CQ (ICI Derby, England) orVistracryl®, PMMA (FDA MAF 1189). Teflon and tantalum are also noted. Itis also possible to coat eye-contact member 120 with biocompatiblematerials if elements of the eye-contact member 120 are notbiocompatible. In some embodiments, the eye-contact member 120 containspigments or dyes. In particular embodiments, the eye-contact member 120is coated or impregnated with bioactive substances includinganti-inflammatory agents/immunomodulating agents and/or anti-infectiveagents. Particular eye-contact members will contain radio-opaque,radioactive, fluorescent, NMR contrast or other reporter materials.

In an exemplary embodiment of the invention, the contact member 120 ismade from poly(methylmethacrylate), or PMMA. The internal contour 122may replicates the curvature of a typical photocoagulation lens used inophthalmology practice (e.g. Haag-Streit). In operation, a lubricant(e.g., Genteal) may applied to the lens to keep the eye moist during theprocedure. A light vacuum (e.g., from about 10 to about 50 mm Hg, andpreferably less than about 25 mm Hg) may applied to the device throughthe vacuum tube (e.g., by a spring loaded syringe device, which may beclipped to patient clothing), and the eye-guide positioner 600 may applya bias force against the eye (e.g., spring loading of arm 180). Thecombination of light vacuum and light bias force has been demonstratedby inventors herein to provide adequate eye stabilization, whilepromoting patient comfort. The I Guide may have a breakaway feature(e.g., a axial post-and-ferrule connection of lens 120 to post 222) thatallows the patient to exit from the positioning arm quickly andseamlessly as needed (e.g. during a sneeze). In this case, the vacuumand cup 120 may remain on the patient in the event of movement away fromthe positioning arm, allowing easy re-attachment. A certain degree ofrigidity, or hardness, of eye-contact member 120 is of use in physicallycoupling with the eye and with the pivot which attaches to the controlarm as described in further detail below. However, the eye-contactmember 120 includes, in certain embodiments, a certain degree offlexibility, or softness, such that the eye-contact member 120 has adegree of flexibility, but still retains an arcuate shape in its restingposition. In some embodiments, eye-contact member can break away fromthe contact device at a predetermined position along connector 222, asdescribed in greater detail below.

With continued reference to FIGS. 41A-B, the contact member forms, witha back plate 121 of the contact device, an internal reservoir 122 bywhich a negative pressure (partial vacuum) applied to the device,through a vacuum port 210, is distributed across the contact surface ofthe device, as can be appreciated. The vacuum port is connected to asuitable vacuum source though a tube 275. In this embodiment, the vacuumport 210 is positioned through the eye-contact member 120 such that anair or fluid communication space is formed through eye-contact member120 to allow air trapped between eye-contact member 120 and the anteriorsurface of the cornea 200 of eye 130 to be reversibly removed, therebyreversibly engaging the eye-contact member 120 with the anterior surfaceof the cornea 200. In an alternative embodiment not shown, vacuum port210 is attached to connector 270 which can contain a hollow lumen alongaxis 235 through eye-contact member 120 such that air betweeneye-contact member 120 and the anterior surface of the cornea 200 iscapable of being reversibly removed as described above. Vacuum orsuction assistance is useful for locating and adhering the scleral lensbase on the eye 130 of the subject and securing the contact device 110to the subject's eye 130. Once in a desired treatment position, thecontact device 110 can couple with the system 100 during the treatmentprocedure, as described below. Following treatment, the contact device110 can be decoupled from the system 110 and removed from the subject.

In one preferred embodiment, negative pressure applied to the eye, forexample, a negative pressure of 20-50 mm Hg, is effective to stabilizethe position of the eye on the device, that is, substantially preventmovement of the eye with respect to the device, but by itself is notsufficient to hold the eye-contact device on the eye. Rather, thecontact device is secured to the eye by a biasing force acting to biasthe device against the patient's eye, acting in combination with thenegative pressure applied to the eye by the device. In the embodimentillustrated, the contact device is secured to the eye by the biasingforce acting through arm 180, where the negative pressure applied to thecontact device functions to prevent the eye form moving with respect tothe device. As noted above, the contact device is typically biasedagainst the eye with a force of between about 1-25, typically 5-25grams, by a biasing spring, electromagnetic force, or the like. Theadvantage of this system is that the negative pressure applied to theeye can be substantially less than that which would be required if thevacuum alone were acting to hold the device to the eye, and thissubstantially lower negative pressure increases comfort and reducesirritation and deformation of the front portion of the eye. The biasingforce is illustrated in the figures, e.g., FIG. 40A-B, by an arrow 119,which indicates the direction of action of the force in the figures.

When the eye-contact member 120 contacts eye 130, negative pressure isapplied to remove air from between the eye and contact member, tostabilize the position the eye 130 with respect to the contact member. Aprimary vacuum fitting is in fluid communication with the air passage. Avacuum line 275 is connected to the vacuum port 210. Additionally, avacuum pump is in air or fluid communication with the vacuum line 275for evacuating the air trapped between eye-contact member 120 and thecorneal surface 200. Collectively, the vacuum port 210, line 275, andpump (not shown) constitute a primary vacuum subsystem. The degree ofstrength of the vacuum required to seal can be varied, and preferablycontrollably and continuously monitored, by the system of the invention.In one embodiment of the invention, between about 0.5 mm Hg and about 50mm Hg are utilized to provide the negative pressure effective tostabilize the position of the eye with respect to the contact member120. Preferably, the vacuum is between about 20 mm Hg and about 50 mmHg. More preferably, the vacuum force applied is about 25 mm Hg and ismonitored by pressure sensors and/or by directly monitoring the vacuumsource. In some embodiments, the pressure is held passively, forexample, by a bladder. The bladder can be produced such that it canapply a given maximum pressure.

It should be noted that the vacuum pressures described herein aredramatically lower than are used in many prior art forms of ocularsurgery, such as laser radial keratotomy. This system having aspects ofthe invention also avoids the need for temporary paralysis of the eye,and avoids patient discomfort. Contact member 122 may be mechanicallybiased by a light force (such as a spring applied to support arm 180) tobear against the eye, assisting in maintaining engagement with thecornea, without heavy suction.

By engaging the contact member 120 with the eye 130, the eye 130 becomesfixed in a first position, the patient unable to move the contact memberwith intra-ocular movements. The contact member can, however, be movedusing control arm 180; the movement by the control arm rotates the eyethrough the eye-contact member. Thus, one embodiment of the inventionincludes substantially stabilizing the eye 130 in a selected positionwith the eye-contact member 120.

FIGS. 42A-D depicts perspective views of the contact device with thecontrol arm attached having aspects of the invention. As shown in thefigures, a preferred embodiments of contact device 110 includes a pivotjoint or connector 220 which accommodates pivot movement between thecontact member and positioning arm 180, as the arm moves the contactdevice to a desired orientation in the external coordinate system. Inone embodiment, pivotable connector 220 is a spherical or ball pivotjoint which allows rotation in three dimensions. In the example shown,positioning arm 180 may be releasably coupled to the contact devicethrough a stem-and-socket arrangement which fastens the end of arm 180to a socket formed in ball joint 220.

FIG. 42 C-D show an alternative embodiment in which the contact memberor lens 320 is supported from one or more off-center points (e.g., byside-post 302) so that a central portion may be transparent, permittingretinal imaging while the eye is engaged by device 312 (e.g., by afundus camera, which may be employed as a module in system 10, or may beseparate). With a contact member or lens 320 which is transparent in itscenter, direct imaging of the retina can be performed so that ratherthan fiducials, the retinal coordinates and movement can be imageddirectly. Pivot point 220 is off center and post 302 is off center aswell. The apex 320 a of the lens 320 is free to transmit incident andreflected light, allowing the retina and other ocular structures to beseen through the lens 320.

Method of Use of Eye-Guide in Carrying Out Treatment

FIG. 43A is a flow chart illustrating one method of utilizing the systemfor stabilizing and positioning an eye for treatment. It should be notedthat the devices described having aspects of the invention may be usedin a wide variety of ocular treatment methods. FIGS. 43B-E are diagramsof an eye associated with the radiotherapy system, illustrating examplesof steps included in the flowchart of FIG. 43A. As illustrated in FIG.43A, a preferred method 2500 of employing the system described aboveincludes:

Step 2510

Prepare Eye—

Preparing a subject's or patient's eye for treatment which can includedelivering an anesthetic, taping the upper or lower lid, fitting anopposite-eye patch, measuring biometric parameters such as axial length,corneal diameter, etc. Optionally the eye may be dilated, particularlywhen employing alternative device/method embodiments having aspects ofthe invention which include integrated retinal imaging optics (notshown) with radiotherapy treatment system 10 (e.g., OCT or funduscamera).

Step 2520

Position and Secure Head—

Following preparation, the subject's head is secured in a suitableposition to the system, such as in head and chin rest 160 and headfastening 161. This assembly may include a gating interlock detector(see Step 2565) to assure it remains engaged during radiation emission.Other patient position detectors may optionally be included, such ascontact-sensitive hand grips 163.

Step 2530

Position Eye Holder on Subject's Eye—

The eye contact member or eye-guide 110 is then positioned on thesubject's eye. The eye-guide contact lens 120 and/or eye surface may becoated with an ophthalmic lubricating solution or gel (e.g., GenTeal®formulations, produced by Novartis Ophthalmics).

As further shown in FIGS. 20 and 43B, the limbus 26 comprises thegenerally circular boundary of sclera 17 and cornea 35, the limbus lyingsubstantially within the projected plane 26 a. A corneal tangent plane35 a projected parallel to limbus plane 26 a intersects the corneacenter 35 b closely adjacent the limbus center 26 b. The geometric axis2810 of the eye 30 may be defined as an axis through the center 26 b ofthe limbus 26, perpendicular to the center 35 b of the external surfaceof cornea 35, and intersecting the surface of retina 1435 at retina pole1436).

The alignment in step 2530 includes engaging the eye-guide 110 with eye30 so that the eye-guide has a known or measurable orientation andposition relative to the center 26 a of limbus 26. In the example shown,the eye-guide contact portion or lens 120 may advantageously be formedto be substantially circular and concentrically aligned with aneye-guide center axis 110 a. Similarly, the central axis 110 a of theeye-guide 110 in the example shown is substantially collinear with theeye-guide support post 222. This symmetry conveniently assists aphysician to positioning of the holder or eye-guide 110 on the eye 30 byvisually aligning the lens 120 symmetrically with limbus 26. In thisposition, the post 222 of the eye-guide 110 is aligned with the centerof the limbus 26 so as to indicate the geometric axis of the eye. Thelens 120 may be transparent, advantageously permitting visualconfirmation of concentric alignment of the lens edge 120 a on thelimbus 26 in embodiments in which lens 120 is larger than limbus 26(i.e., covering a portion of adjacent sclera 17).

However, the lens 120 need not be circular, and the eye-guide supportpost 222 need not be collinear with the eye-guide axis 110 a (seeexamples FIGS. 42C-D). As described herein in detail, camera image-basedfeature recognition methods having aspects of the invention provide forcomputer processor determination of the position of the center 26 b oflimbus 26, and fiducials located on eye guide 110 may similarly betracked to determine the relative position and orientation of eye-guide110 with the center of limbus 26. These determinations provide anon-visual method to guide and confirm the alignment of the eye-guide110 with the geometric axis 2810 (see step 2540).

The eye-guide placement and alignment can be performed by a physicianwhile observing the both the holder and the eye of the patient directly,or on a computer monitor, or both of these interactively. Alternatively,an imaging camera-processor of imaging system 410 can determine thecenter of the limbus automatically and aid in the positioning of theholder with its center aligned with the center of the limbus (see axialcamera view of FIG. 43C(2)). In some embodiments, the holder ispositioned in place automatically rather than manually by the deviceoperator. Note that at this step the X-ray source positioning system(see 115 in FIG. 33A) need not be aligned with the geometric axis 2810,and is shown in FIG. 43B at an arbitrary relative orientation P1.

Step 2532

Apply Suction to Hold Eye Holder Against Eye—

Once the position of the holder or eye-guide lens 120 relative to thelimbus is determined, suction may be applied through the holder toappose it to the eye. With the holder firmly attached to the eye, theholder (and eye) can be moved into position relative to the treatmentdevice in known coordinates within the system. Note that the degree ofvacuum suction is selectable, and greater or lesser levels may beemployed. In the embodiments described in detail, a relatively lightsuction (e.g., about 25-50 mm Hg), has been shown to adequately couplethe eye-guide lens 120 to the patient's cornea 12. Such modest levels ofsuction may promote patient comfort and acceptance of treatment.

Step 2534

Quick Release of Control/Support Arm from Eye-Guide Contact Lens—

As described above, a quick release is built into the contact device insome embodiments of the invention. In case of an emergency or fatigue,the patient can release from the holder by a applying a modicum of forcewhich results in the eye-contact member or lens 120 releasing orbreaking away from the remainder of the eye-guide device 110. In such acase, the method step returns to the step prior to positioning andsecuring the head 2520, or to the step of positioning the eye-guidecontact device on the subject's eye 2530, as indicated in FIG. 43A.

Step 2540

Align and Stabilize Eye—

As shown in FIG. 43C(1), the treatment device and positioning systemaxis is adjusted as needed to be positioned relative to the eye so as tobring as to bring the X-ray source positioner reference axis (system Zaxis) into alignment with the geometric axis of the eye. In the figures,the system axis when aligned relative to the eye geometric axis 2810 isdepicted as P2. The movement, indicated in the figure as M(x, y, Φ, θ),may include movement or rotation of either or both of the patient's headand/or eye, and alternatively or in combination, may include movement orrotation of the treatment system components. For example with referenceto FIGS. 33A, 40A and 40B, either one or both of the patient's head, eyeand/or treatment system 10 may be moved so as to accomplish alignment.

In certain embodiments, the adjustments may include principally X and Ydirection adjustments of eye-guide positioner 600, which may include amanual or powered multi-axis micro manipulator. An auxiliary display(see 503 b in FIG. 1B) may be positioned to give an physician imagingsystem feedback while operating the eye-guide positioner 600. With thehead stable, movement of the eye guide 110 in the X and Y direction byeye-guide positioner 600 may be used to rotate the eye geometric axis2810 (e.g., by rotating the eye globe in the orbit) to lie parallel tothe reference axis of positioning system 115 (system axis). Movement ofthe positioning system 115 in the X and Y direction can then be employedto bring the two axes into collinearity. Alternatively or additionally,the system axis may also be rotated to align parallel with an initialorientation of eye geometric axis 2810. Additional adjustments may beprovided to adjust the patient's head in rotational degrees of freedom,such as rotation in the X-Y plane. However it has been demonstrated thatproviding a comfortable but firm head and chin restraint assembly 160typically is effective to stabilize the patient's head in a generallylevel and horizontal orientation. See examples shown in FIGS. 1-2including chin rest 172, forehead support 171 and head fastener 173,preferably used together with adjustable patient seating height.

FIG. 43C(2), depicts an example of a view as captured using an Z-axiscamera (e.g., camera 401 in FIGS. 34-35) showing an example contactdevice or eye-guide 110 positioned on patient's eye 30 (see FIGS. 46 and48). The eye-guide post fiducial 1 is shown centered on the Z axis andthe left and right hand support bar fiducials 2 and 3 are shownhorizontally aligned and equally-distant from the post fiducial 1,indicating that the eye guide is aligned parallel and coaxially with thecamera axis. This alignment is confirmed and calculated automatically byimage recognition software from captured camera images by the systemprocessor 501, and such data may be displayed as a image superimposed ona camera image to the operator (display 502). Note that in alternativeembodiments employing a Z-axis laser pointer or beacon (403 in FIG. 34,see FIGS. 53A-B), the eye-guide 110 may be positioned by coaxiallyaligning the reflected laser spot.

Note in FIG. 43C(2) that eye-guide contact lens member 120 is shownpositioned slightly off-center with respect to the limbus 26 (boundaryof iris 24 and sclera 17 on patients eye 30). The image processor 501may also track the limbus position as described herein, and compute adivergence of the center of the limbus from the Z alignment axis(indicated as δx and δy). This divergence may be automatically comparedto a preselected tolerance threshold, and also may be displayed to theoperator within the camera image frame.

Step 2542.

In the event that the limbus divergence is determined to be unacceptable(either at Step 2540 or at any other step), Steps 2530 through 2540 maybe repeated as shown by the return arrows on flow chart FIG. 43A.

Note that the processor 501 may be programmed to monitor eye cameraimage data (e.g., cameras 401, 402) to re-determine limbus-to-lensalignment on an ongoing basis during treatment, and to determine anerror condition (one example of patient-interlock diagnostic in Step2565) linked to radiation or X-ray source 420 so as to trigger gatingwhen a selected alignment threshold is exceeded.

Note that in certain embodiments having aspects of the invention, atreatment system reference coordinate system may have an arbitrary, butknown, orientation/position to an eye anatomical reference, as shown inFIG. 43B. From this known eye reference orientation/position, suitablemathematical transformations may be performed, e.g., by a controlprocessor of a robotic positioner, to move an X-ray source to a selectedtreatment orientation with respect to an treatment target. However, itis advantageous in ocular radiotherapy devices having aspects of theinvention, to have a principal mechanical movement axis of the X-raysource positioning system aligned parallel to, and preferablycollinearly with, the geometric axis of the eye. For example, thegeometric axis of the eye 2810 may be aligned, as shown the Z axis ofpositioning system 115, which may also be the θ rotational axis. Inembodiments described in detail herein and illustrated in FIGS. 43C-E,such an alignment method is conducive to precision calibration andcontrol of X-ray source movement. With this initial system alignmentrelative to eye anatomy accomplished (FIG. 43C), only a limited set ofsubsequent movement ranges and directions are required for carrying outa stereotactic treatment plan. For example, these may include a smallX/Y shift to treatment axis 2820 (step 2550, FIG. 43D), small Φ and/or Zadjustment to target convergence angle and limbus clearance, and amodest θ adjustment for each subsequent beam path (step 2555, FIG. 43E).Such limited and constrained motion serves to minimize mechanicalbacklash, uncertainties and vibration, and to maximize accuracy,repeatability, patient confidence and intuitive operation.

Step 2550

Position Treatment Axis—

A radiotherapy treatment plan for an ocular condition may be developedspecifying a target location relative to an anatomical reference pointsuch as the macula or fovea as described herein (see also the examplesand description in U.S. patent Ser. No. 12/100,398 filed Apr. 9, 2008,which is incorporated by reference).

In certain embodiments, the X-ray source may be positioned for treatmentwhile maintaining the system Z coordinate axis aligned with thegeometric eye axis 2810, either for central axis targets, or by suitablerobotic controls transformations for off-axis targets.

However, in the embodiments described in detail herein, and as shown inFIG. 43D, the system Z-axis (e.g., the Z axis of X-ray sourcepositioning system 115) may be shifted to realign with treatment axis2820 which intersects the center of treatment target 318. The systemaxis thus realigned is indicated as P3 in the figure. In this example, alesion of the macula is treated by radiation to a target 318approximately centered on the fovea. An exemplary treatment plan maydefine offsets relative to the pole of the retina (intersection ofgeometric axis 2810 with the retinal anterior surface), the offsetsbeing defined as X and Y movements in the plane tangent to the retinalpole (dx, dy). The detail diagram indicates offset dimensions taken fromfundus images of a representative sample of persons, defining meanvalues of offsets of the fovea from the retinal pole of about 1.16 mmand −0.47 mm respectively, although these values are purely exemplary.In this example, the X-ray source positioning system 115 is moved thespecified dx and dy offsets by action of the X and Y axis actuators (seeFIG. 37), so as to shift the system Z axis (translate without rotation)so as to intersect the defined target 318.

Step 2555

Position Beam and Verify Limbus Clearance—

FIG. 43E illustrates the motion of the X-ray source to carry out anexemplary stereotactic treatment following the shift of the system Zaxis to intersect the target 318, as depicted in FIG. 43D.

The Z and Φ axis actuators may be moved to orient the collimatorassembly 118 so that the beam axis 1400 intersects the Z axis at thetarget 318, forming a triangular arrangement (see FIGS. 34-38). With theZ and Φ axis positions thus fixed (values Z₀ and Φ₀), the collimatorassembly 118 may be subsequently re-oriented solely using the θ actuatorto selected treatment beam positions (e.g., beams 1, 2 and 3 at valuesθ₁, θ₂ and θ₃ respectively) to align the beam axis 1400 to propagate totarget 318 and intersecting the body surface at respective selected beamentry points (e.g., sclera beam-spots 311). Note that while it isadvantageous to re-orient the collimator assembly 118 for multiple beampaths by single degree-of-freedom motion, it need not be so, andalternative embodiments may provide for more complex movement.

The clearance c of the (each) X-ray beam 1400 at scleral entry spot 311may be confirmed both visually by the operator and/or by imagerecognition by the processor 501. As shown in greater detail in thecamera-frame image of FIG. 43C(2), a laser beacon 1410 (see FIG. 36) maybe aligned along the beam axis 1400 (the intended beam path as aimedprior to X-ray emission) to create a small visible spot on the sclera ofknown position relative to the beam 1400 (e.g., concentric), the spotlying within the camera frame. The laser spot may be recognized byprocessor 501, its position calculated, and compared with the trackedposition of limbus 26, so as to calculate the beam-center-to-limbus-edgeclearance c. The clearance c may then be compared with a minimumtolerance (optionally also a maximum tolerance). For example, based on apredicted collimated beam radius of about 1.5 mm at the sclera, aselected limbus minimum margin of 2.0 mm may be determined by a value ofc≈1.5+2.0=3.5 mm. The beam margin from the limbus may be specified in atreatment plan, e.g., from about 1 to about 5 mm. The X-ray beam radiusat the sclera (e.g., from about 0.5 to about 5 mm) may also bepredicted, such as by calculation of collimator geometry and/orradiographic measurement as described in detail herein. The clearance cmay be adjusted if needed, e.g., by small movements of the X-ray source420 in Z and/or Φ directions.

Step 2560

Perform Treatment with Eye Tracking—

X-ray treatment may be administered according to the treatment plan,such as at a pre-selected beam configuration, intensity and spectrum,the beam being emitted for a time interval selected to deposit a desiredabsorbed dosage to the target. Multiple beams may be emittedstereotactically to delivery a desired total target dosage, whileexposing non-target regions (such as sclera beam entry spots 311) toless dosage than that of an equivalent single-beam treatment.

During treatment, the eye position relative to the system 10 may becontinually tracked as described in detail herein and the eye positiondata so obtained by be automatically monitored by processor 501 on areal time basis as treatment progresses, including calculation of themotion of target and other eye anatomy (an resultant dose variation)based on eye tracking motion data. See description regarding FIGS.49-54, and detail description in co-invented Application No. 61/093,092filed Aug. 29, 2008 and well as the other applications which areincorporated by reference. As described below with respect to Step 2565,such eye tracking data and calculations may serve as a basis forradiation interruption or gating.

In the embodiments described in detail herein, the X-ray collimatorassembly 118 may remain fixed during the emission of an X-ray treatmentbeam. However, in alternative embodiments, positioning system 115 may beconfigured to provide real-time repositioning of the X-ray source duringX-ray emission, for example, to compensate for residual motion of theretinal target during treatment. Alternatively In certain embodiments,all or certain ones of the actuators described with respect to FIG. 37for positioning of the X-ray source (X, Y, Z, Φ and θ of positioner 115)may be used to re-position the X-ray source so as to compensate formotion of the retina. Alternatively, additional actuators and/or degreesof freedom may be provided so as to provide fast-response, small-range(Vernier) adjustment of the X-ray beam orientation (e.g., re-aiming theretinal beamspot) and/or shaping (e.g., responsively blocking a portionof the beam spot, such as proximal to the optic disk), so as to permitrapid adaptation of the beam to compensate for a moving retinal target.Such embodiments are describe further in co-invented Application No.61/093,092 filed Aug. 29, 2008, which is incorporated by reference.

Step 2562.

For multiple beam path or stereotactic treatment, method Steps 2555-2560can be repeated as indicated by Step 2562 until a desired treatment iscompleted, for example for a pattern of three stereotactic beams asdescribed in detail herein.

Step 2565

Interrupt Radiation (Trigger Gating)—

During the course of Step 2560 as radiation is being emitted along beampath 1400, radiation may be interrupted (gating of X-ray source 420) inresponse to selected criteria, such as threshold values of measuredcriteria, discrete system-level diagnostic error or failure states, orpatient-level interlock or diagnostic triggers. Upon triggering ofgating, various devices may be used to interrupt X-ray or otherradiation emission, as described herein.

Step 2567.

Following gating, corrective action may be taken as indicated independing on the particular triggering cause (may require repeating oneor more preceding steps), and treatment irradiation then resumed until adesired beam fractional dose is delivered.

(i) In motion-threshold gating, such as Subsection 1 below, all orportions of alignment and positioning steps 2540-2455 generally arerepeated to bring the beam center into alignment with target center,prior to completing the treatment fraction.

(ii) In some cases, such as transitory system conditions in Subsection 2below, the corrective action may involve brief system corrections notrequiring repetition of pre-radiation steps 2555 or before, andtreatment may be resumed at step 2560. In other cases, the positioningactions included in steps 2450-2550 may not need to be entirelyrepeated, but verification of alignment and position (visually or byimage processing) may be desirable before resuming treatment.

(iii) if the gating is triggered by decoupling of limbus 26 andeye-guide lens 120, as in the example of Subsection 3 below, correctiveaction may include repeating the eye-guide positioning steps 2530 and2354 as well as steps 2450-2550.

Examples of gating criteria may include one or more of:

1. Exceeding Retinal Motion Threshold.

As described herein and in the incorporated applications, the eyetracking data may be employed to determine one or more discrepancy orerror values based on a target movement or motion-related dosedistribution, such as a maximum target displacement, a cumulative retinadisplacement vector, a dose distribution indicator, or the like. Theerror value may in turn be compared on a real-time basis with a gatingthreshold value to trigger a gating event. Optionally, eye trackingalgorithms may be used to track motion or dose relative to non-targetstructures, such as the limbus, lens of the eye, optic nerve and thelike, with respective gating thresholds.

(a) In a one motion-threshold example embodiment for a retinal targetregion, the error value may be the current scalar magnitude of asummation vector representing cumulative retina target motion derived ona time increment basis (e.g., camera frame-by-frame rate or a selectedsub-sampling rate) from eye tracking data. For example the vector inputsmay include components in the X and Y directions of the retinal targetplane, indicating the X and Y deviations at each measured time of thebeam center from the target center. The vector summation accumulatesthese components as directional vector quantities, the scalar magnituderepresenting the radial distance from the target center of the summationvector (square root of the sum of the squares of the components). Such asummation vector magnitude represents the time-weighted cumulativedisplacement error in the position of the beam-spot center from theplanned retina target center point. The vector may be linear, oralternatively have quadratic or other non-linear distance weighting soas to de-emphasize small fluctuations in position (e.g., jitter orvibration) relative to larger, continuous displacements. Upon reaching apre-selected scalar magnitude threshold, gating (interruption) of theX-ray source can then be triggered.

(b) A calibrated “motion-free” dose distribution may be determinedexperimentally and/or computationally (e.g., Monte Carlo simulationand/or radiographic beam-spot measurements) representing the dosedistribution either at the target region (e.g., macula surface) or atany other tissue location within or adjacent to the radiation beam path.From the calibrated dose distribution, an equivalent time-increment dosedistribution may be determined for a desired time increment (e.g. videoframe rate). Retina or other tissue motion can then be derived from eyetracking data as described herein, and such motion data can be used tomodulated with time-increment dose distribution so as to yield acontribution for each time increment to a cumulative dose distributionaccounting for measure eye motion. Such motion-modulated dosedistribution may be used to validate or determine a motion-thresholdvalue as in 1(a) above by determining the dose distribution at thegating trigger point. Alternatively the motion-modulated dosedistribution may be used to evaluate the adequacy of treatment doselevel within the planned target region 318.

(c) Alternatively, the motion-modulated dose distribution of 1(b) may bedetermined on a real-time basis at any desired anatomical locationwithin the distribution, and such dose may compared to a dose-thresholdbe used to trigger gating. For example, a maximum cumulative dose at theedge of the optic disk may be used to trigger gating.

(d) Alternatively or additionally, the real-time determined cumulativedose distribution of 1(c) may be evaluated within the planned targetregion, and may be used to trigger termination of treatment at a desiredtarget treatment profile, including motion-related eye-dose distributioneffects. Examples include triggering gating-termination upon (i)reaching a selected maximum treatment dose level at highest-dose pointin a defined target region; (ii) reaching a selected minimum treatmentdose level at the lowest dose point within a defined target region;(iii) reaching a selected average dose within a defined target region;(iv) a combination of these (e.g., reaching at least a selected averagedose after achieving a selected low-point minimum); or the like.

2. System-Level Functional Diagnostics.

Gating may be triggered by error or failure conditions such as loss ofeye tracking by the system, loss of limbus tracking, or othersystem-based failure deemed justification for interruption of radiationtreatment, e.g., due to electronic conditions, camera conditions,lighting conditions, inadvertent blocking or interference with imaging,and the like. Alternatively or additionally, processor 501 may determineand monitor a selected number of different diagnostic conditions whichcan be used to trigger gating, such as X-ray tube parameters, lightingparameters, laser pointer 1410 position tracked relative to the limbus(limbus clearance), and the like.

3. Patient-Level Interlocks.

Alternatively or additionally, processor 501 may determine and anmonitor a selected number of patient-based interlock or diagnosticconditions which can be used to trigger gating.

(a) These may include specific patient interlock sensor signals, such asindicating disconnect of head restraint fasteners, disconnect ofeye-guide lens mounting (see step 2534); patient hand grip 163 contactsensors (See FIG. 33A), and the like.

(b) The patient-based condition may also be determined by imageprocessing/recognition from one or more cameras or other remote sensors.For example, the relative positions of eye-guide 110 and limbus 26 maybe monitored continuously during treatment via camera-based eye trackingand compared against a selected threshold indicating disconnect ordecoupling of the eye-guide lens 120 from the patients eye (such as bysliding of the lens over the cornea). An error condition may bedetermined so as to trigger gating of radiation. (c) In a furtherexample, transitory “blinking” compensation gating embodiments aredescribed in co-invented Application No. 61/093,092 filed Aug. 29, 2008,which is incorporated by reference. The transitory gating embodimentscompensate for sudden, brief, large magnitude, generally verticaldisplacements which result from involuntary blinking or spasmodicmovements of the eye, typically followed by a quick return to agenerally well-aligned eye position. These eye movements may be rapidlydetected by image-based eye tracking so as to trigger a rapid-responseradiation gating. Treatment radiation may be automatically resumed,either after a fixed time delay or an automatic realignmentconfirmation. This “blinking” type gating may be used independently orin combination with retinal motion threshold gating described inSubsection 1 above.

Step 2540

Release Eye Holder—

Following treatment, the patient may be released from the eye-guide 110(e.g., release of vacuum suction) and head restraint 160.

Pixel-Level Image Alignment Methods.

In certain embodiments having aspects of the invention, the imagerecognition and processing may be conveniently and advantageouslyperformed on a digital pixel-level of camera resolution based on cameraimage signals (e.g., cameras 401, 402), such as a selected video framerepresenting an image at a defined image capture time. The eye alignmentmethod of Step 2540 may be applied similarly to the alignment of otheranatomic features as a step in carrying out treatment with a radiationdevice.

Conventional video frame image data may be stored for processing in amanner known in the electronic arts, such as by defining atwo-dimensional array of pixel data in a computer memory, wherein eacharray element is mapped to a particular pixel position of the cameraimage and wherein each array element is associated with one or aplurality of values indicating pixel color and/or intensity. Forexample, a 24-bit RBG color-encoded pixel values of an array for a1000×1000 pixels image dimensions may be stored. Where the image captureis focused and delimited by a specific area of interest, (e.g., aportion of the patient's face including an eye, eye lids and adjacentskin surface), the pixel position may be mapped to a particular point onthe area of interest. For example, where the area of interest is anapproximately 10 cm×10 cm area of the patients face, each pixel of a 1Mega-pixel image represents about region of about 0.1 mm×0.1 mm, orabout 100 micron resolution. A 4 Mega-pixel image represents aboutregion of about 0.05 mm×0.05 mm, or about 50 micron resolution.

The imaging camera may conveniently be aligned with the radiotherapycoordinate system axes (or alternatively, at a known orientation andposition relative to the coordinate system). For example, and axialcamera may be aligned so that the camera optical axis is parallel to thesystem Z axis, and so that the center pixel of the camera sensor chipcorresponds accurately to the system Z axis. For this orientation, thecamera “sees” its field of view in direct relation to the system X-Yplane origin, as shown in FIG. 43C(2). Deviations and directions ofimaged features may then be measured in pixel scale in this referenceframe.

The storage of image data may continue for subsequent video frames. Ifdesired, image processing and feature recognition may be carried out ona real-time basis on all, or a selected sub-sample, of the capturedvideo frames. Camera sensor resolution and image size (e.g.,conventional CCD image sensor chip), frame capture rate, and otherimaging parameters may be selected in consideration of associatedoptical and mechanical components, to optimize system performance, cost,speed and the like, as is known in the electronic arts.

Referring to the axial camera view shown in FIG. 43C(2), in an examplesub-method embodiment, the processor 501 may be programmed with suitablesoftware code, acting on image data in computer memory, to carry out allor a portion of the sub-steps of an image alignment algorithm,including:

(a) Identifying a pixel of the image representing the eye-guide centralaxis. For example, the processor may:

(i) determine the portion of the image including center-post fiducial 1(e.g., by contrasting edge detection);

(ii) determine the geometric center of the fiducial image area; and

(iii) select the pixel lying closest to the fiducial center.

(b) Determining that the eye-guide 110 is aligned with the camera(system Z axis). For example, the processor may:

(i) repeat step (a) with respect to each of fiducials 2 and 3 so as toselect a pixel representing the center of each fiducial;

(ii) calculate the horizontal (X) center-to-center the distance betweeneach of fiducials 2 and 3 and fiducial 1 (e.g., count number ofintervening pixels);

(iii) determine whether fiducials 2 and 3 are equidistant from fiducial1 (no horizontal tilt) [*optionally display any error magnitude tooperator];

(iv) calculate the vertical displacement (Y) of the fiducials 2 and 3from fiducial 1;

(v) determine if fiducials 2 and 3 lie on a horizontal line includingfiducial 1 (no vertical tilt) [*optionally display any Y and θ errormagnitudes to operator];

(vi) determine if the pixel representing the eye-guide center is locatedat (0,0) of image system Z axis (center pixel of camera image)[optionally display any X and Y error magnitudes to operator];

(vii) determine, if (iii), (v) and (vi) are true, that eye-guide 110 isaligned with the system Z axis [*optionally compare with selectedtolerance thresholds and display compliance or non-compliance tooperator];

(c) Determining the location of the center of limbus 26 in the systemcoordinates. For example, the processor may:

(i) determine the portion of the image including all or the exposedportion of the limbus boundary (e.g., by contrasting edge detection) andidentify the pixel locations corresponding to the limbus boundary image;

(ii) mathematically determine a “best fit” shape corresponding to limbusboundary data, for example using boundary pixel locations as inputs todetermine an equation for a circle or ellipse with lowest errorfunction;

(iii) calculate the center of “best fit” shape, and identify the imagepixel closest to center.

(d) Determining any deviation of the location of the center of limbus 26from either or both of the system Z axis. For example, the processor maycalculate the horizontal (X) and vertical displacement (Y) of the limbuscenter from pixel representing the system Z axis (e.g., by countingintervening vertical and horizontal pixels) [*optionally displaying theX and Y values to operator].

(e) Registering the positions and/or orientations determined in steps(a-d) of one or both of eye-guide 110 and limbus 26 in a virtual eyemodel, e.g. eye anatomic geometry stored in computer memory. Forexample, the eye model may additionally include measuredpatient-specific data and/or imagery such as eye axial length, and ascaled OCT or fundus image.

(f) Calculating the position of the retina (or other structures) in thesystem coordinates based on the registered eye model.

As described above with respect to FIG. 43A, the placement of eye-guide110 relative to the limbus 26 on the eye surface may be adjusted untilthe limbus-to-lens alignment (measured step (d) above) is reduced to asclose to zero as is desired. Likewise, alignment of eye-guide 110relative the system Z axis may be adjusted (e.g., by positioner 600 inFIG. 33A) until the eye-guide alignment error (measured in step (b)above) is reduced to as close to zero as is desired.

A related method having aspects of the invention, including an algorithmfor aligning a body part with a radiation device, may be summarized: (a)defining a normal axis to said body part; (b) aligning said normal axisto a pixel on a camera image visualizing said body part; and (c) linkingsaid pixel on said camera image to a coordinate frame of a roboticpositioning system thereby linking said normal axis of the body part toan axis of the robotic positioning system.

The algorithm may further comprise determining the distance between saidbody part and said robotic positioning system wherein said distance ismeasure along said normal axis. The algorithm may further comprisedefining a normal step comprises locating fiducials on said body part.The algorithm may include that the detection of said fiducials directssaid aligning of said normal axis, such as where the fiducials areattached to a device which contacts the sclera of an eye, and which mayhave a contact member fitted to the limbus of the eye. The algorithm mayinclude that an axial length of an eye is used to define a position on aretina of the eye and said position is utilized to define movement to amacula from said position.

Radiometric Confirmation of Eye Alignment and X-Ray Dose Targeting

FIGS. 44A-B depicts a method of confirming an embodiment of aradiotherapy treatment plan having aspects of the invention. FIG. 44Aillustrates a cadaver eye 30 which has been fixed in a mounting 500,configured to be aligned with radiotherapy system 10 using a suitablemechanical support (not shown) in generally the manner and orientationshown in FIG. 35. The mounting 500 positions the cadaver eye as, ineffect, a phantom eye for purposes of confirming both eye alignmentmethod and the dosimetry of the treatment system. FIG. 44A shows thatthe cadaver eye 30 has been partially dissected to expose the tissueadjacent the posterior retina, so as to permit a backing of radiographicfilm 502 to be positioned behind the eye parallel to the retina.

The procedure includes the following: The eye in mounting 500 with filmis mounted in the eye alignment and stabilization system 625 (see FIGS.39 and 40 for example) by a suitable mechanical support (not shown), andthe eye is aligned using the methodology described with respect to FIGS.43A-E, is the same general manner as the alignment of the eye of a humanpatient. The eye-guide (represented by eye-guide lens 2860 in FIG. 44A)is applied to the cornea so as to be centered on the limbus, vacuumsuction is applied, and X-ray source 420 is moved into treatmentposition as shown in FIG. 35. As with the treatment plans describedherein, the X-ray beam is aligned to a treatment axis 2820, which ispositioned relative to eye geometric axis 2810 by a pre-determinedoffset 2850.

A series of three treatment beams are applied to eye 30 (see FIGS.30A-B), so as to expose the radiographic film 502 adjacent the retina soas to produce an exposed spot 504 indicative of the target absorbed dosedistribution. The radiographic film is formulated to produce a visiblespot, permitting a marking pin 506 to be inserted through the film intoeye 30, in this example at the center of spot 504, so as to register andmaintain the orientation of the film 502 as exposed with the eye tissue.

Eye 30 is then dissected along a retinal section as shown in FIG. 44A toexpose a the posterior retina, registered to the exposed film 502. Theflattened retinal superimposed on exposed film is depicted in FIG. 44B.The retinal geometry is shown in the detail on the left at the left, theretinal dissection shown schematically on the right view of the figure.As may be seen, the exposed film spot 504 is substantially centered onthe macular target, covering the 4 mm target region. The spot 504 isalso substantially separated from the optic disk 350. The geometry ofdosage may be compared with the phantom mannequin dose map of FIG. 30C.

The procedure thus confirms the effectiveness of the eye alignmentmethod and ocular targeting methods having aspects of the invention, bydemonstrating that the applied radiation dose is targeted to the maculartissue (and avoiding the optic disk), as provided by the treatment plansdescribed herein.

Eye-Guide Placement and Eyelid Retraction

FIGS. 45A and 46A are drawings of a patient's eye showing an eye-guide110 having aspects of the invention as engaged with the eye in anoperative position, in this case with the eye substantially as itappears when aligned with the eye-alignment axis 2810 of radiotherapysystem 10. The eye-guide lens 120 is shown approximately centered onlimbus 26, the lens being supported by arm 180.

In the example of FIG. 45A, the eye-guide 110 includes a plurality ofreflective fiducials (as further described herein), having two or morefiducials 240 positioned spaced-apart on the lens 120, and one or morefiducials 250 positioned on the crown of center post 222. In thisexample, the center post may also include a mirrored surface 230, whichmay be used to track alignment with a axial pointer beacon or laserbeam, as further described herein (see also FIGS. 40 and 53). Theeye-guide embodiment shown is of the type employed during acquisition ofthe example eye-tracking data shown in FIG. 49A-E. using an eyealignment/tracking system having an alignment-axis-centered low poweredlaser pointer 403 (see FIG. 34).

In this example, the lower eyelid is retracted downward by a retractoror lid speculum 320 a to expose an area of the sclera for treatment beamentry. The upper lid may ride over the eye guide lens 120 upper portion,but the system cameras can effectively track both the lens fiducials240, and detect and compute the image of the limbus (as furtherdescribed), permitting the positions of each to be determinedautomatically (including extrapolations to covered portions shown asdashed lines).

The retractor 320 a is shown in detail if FIG. 45B and includes a smoothand non-abrasive hook-like portion 323 comprising a wire-loop configuredto overlap and engage the eyelid, the hook mounted on a handle portion324. The handle portion may be supported a number of alternative ways(e.g., hand-held, taped to a support, mounting to a base, or the like),but a advantageous alternative is to connect the handle via an elastictether portion 325 to an attachment 326, such as a spring clip or thelike. The tether may comprise a stretchable elastic member, which maycomprise an elastic strap, an elastomeric tube or the like. A terminalattachment is included to mount the tether to a convenient base, such asa spring clip, snap fitting, or the like. Either or both of the tetherlength or attachment position may be adjusted to provide a selectedtether tension acting upon the eyelid. A length-adjustment fitting (notshown) may be included in the tether 325, such as a friction loop,Velcro fitting, or the like.

In certain embodiments, the tether is configured to be attached to thepatient so that the relation of attachment to eye is relativelyconstant, notwithstanding patient movement. For example, the attachment326 may include a spring clip which can be clamped to patient clothingadjacent the face, such as a shirt collar, button hole, pocket, or thelike. Optionally, the tether 325 may include a force-limiting coupling,such as a magnetic or adhesive coupling, the coupling configured torelease if excessive tension is applied to the tether. For example, seeco-invented Application No. 61/093,092 filed Aug. 29, 2008 which isincorporated herein by reference, in particular coupling 327 shown inFIG. 23C of that application.

FIG. 46A shows the alternative eye-guide embodiment 110 as engaged withthe eye in an operative position. The eye-guide shown is of the typedepicted in detail herein and shown in FIGS. 47A-F. The lower eyelid isretracted downward by retractor embodiment 320 d. FIG. 46B illustratesan alternative retractor embodiment 20 b which includes a non-abrasivesmoothly curved or saddle-shaped spoon-like hook member (e.g., aDesmarres-type member) mounted on a handle portion 324. The handleportion may be supported as described above with respect to FIG. 45. Inthe example shown, the handle 324 is mounted to a tether, in this caseby means of a handle with a cylindrical cross section which may beconveniently inserted into a rubber or elastomeric plastic tube, so asto bind to the tube by stretching and friction.

In a further exemplary refractor embodiment shown in FIG. 46A, thesaddle-shaped surface is elongated and configured to provide a curvedborder adjacent scleral X-ray beam spots 311. All or a portion of thebody of retractor 320 c may comprise a radio-opaque material so as toprovide effective shielding of the eyelid and adjacent tissue from strayor scattered radiation during X-ray treatment beam emission.

Detection of Eye-Guide Fiducial Patterns

FIGS. 47 through 52 illustrate various method and device embodimentshaving aspects of the invention using fiducials to determine eyealignment and track eye motion in association with a medical device.FIGS. 47-48 illustrate embodiments of eye-guide devices (110, and 512)for use in a eye stabilizing system having aspects of the invention, andhaving patterned fiducials, and a method of determining orientation byimage recognition.

Turning initially to FIG. 47A, the figure shows a perspective view of anembodiment of contact or eye-guide device 512 including the contactmember 120, spherical pivot 220, mirror 230 and vacuum port 210. In thisembodiment of the invention, the contact device 110 includes one or morefiducial markers 240, 242, 244, 246, 248 which define the geometry ofthe contact device 110 or geometric relationships between the contactdevice 110 and additional components of the system and/or eye asdescribed throughout the specification. The fiducial markers, in oneembodiment of the invention, contribute to the positional knowledge ofthe eye when the contact device 110 is engaged with the eye 130, and acoordinate system is known. Spatial registration can be used record andmonitor the three dimensional spatial position of the contact device 110relative to a known reference point.

In the embodiment illustrated, one or more of the fiducial markers 240,242, 244, 246, 248 includes an imageable fiducial locator. The fiduciallocator is locatable using one or more imaging system modalities. Inthis embodiment, the fiducial is capable of being mounted in or on theeye-contact member 120, such as being either flush to, or recessed from,an outer surface of eye-contact member 120. However, in alternativeembodiments, the fiducial need not be configured for mounting flush toor recessed from contact member 120, and can be mounted to extend fromeye-contact member 120. In another embodiment, one or more fiducials arepositioned on, within, or on the perimeter of mirror 230. This allowsthe mirror 230, along with contact device 110, to be centered or alignedwith respect to the limbus or other ocular structure.

The fiducial may include a liquid or gel housed in a sealed interiorcavity. Preferably, the fiducial is a solid. The solid, gel, or fluidmay be visible by one or more imaging modalities (e.g., MR, CT, etc.).In one embodiment, the fiducial is integrated into the eye-contactmember itself. The imaging fiducial is visible and provides goodcontrast on images produced by at least one imaging modality. In oneembodiment, the imaging fiducial is multimodal (i.e., locatable by morethan one imaging modality), such as by using a mixture of differentimaging fluids, gels or solids that are locatable on different imagingmodalities.

In one embodiment, the one or more of the fiducial markers 240, 242, 244includes a substance that is viewable on a first imaging modality, whileone or more of the fiducial markers 246, 248 includes a substance thatis viewable on a different second imaging modality. In one suchillustrative embodiment, the one or more of the fiducial markers 240,242, 244 includes, or is doped with, a substance having a high atomicnumber (Z), such as barium, titanium, iodine, gold, silver, platinum,stainless steel, titanium dioxide, etc. that provides good contrast on aCT or other radiographic imaging system. In this embodiment, one or moreof the fiducial markers 246, 248 include gadopentatate dimeglumine,gadoteridol, ferric chloride, copper sulfate, or any other suitable MRIcontrast agent, such as described in chapter 14 of Magnetic ResonanceImaging, 2nd ed., edited by Stark and Bradley, 1992, which isincorporated herein by reference.

In an alternative multimodal embodiment, the fiducial marker isconstructed of a substantially solid plastic or other material that ishygroscopic, i.e., capable of receiving and retaining a fluid, such asan imaging fluid that is viewable on an imaging system (e.g., an MRIimaging system or the like). In a further embodiment, the plasticforming the fiducial marker is doped or otherwise includes a substancethat is viewable on a different imaging system, such as, for example, aCT or other radiographic imaging system. Illustrative examples of solidplastics that can be made hygroscopic include, among other things, nylonand polyurethane. Using a hygroscopic material avoids the complexity andcost associated with manufacturing a sealed cavity for retaining animaging fluid. Moreover, by adapting the solid hygroscopic plastic forimaging using a first modality, and by using the imaging fluid forimaging using a second modality, each of the solid and the fluid can beseparately tailored toward providing better contrast for its particularimaging modality.

In a further embodiment of the fiducial markers illustrated in FIG. 47A,the outer surface of one or more of the fiducial markers is reflectiveof light or other electromagnetic energy. Consequently, it is locatableby a camera in an optical positioning system that is coupled to animage-guided workstation (e.g., during subject registration). Oneadditional function of such fiducials is measurement calibration wherethe distance between fiducials is used to calibrate distance on orwithin the eye. In one such example, the outer surface of the imagingspherical fiducial marker includes light-reflective microspheres (e.g.,embedded in an adhesive covering the fiducial or eye-contact member120). In another such example, the outer surface of the fiducial iscovered with an adhesive-backed light-reflective tape, such asSCOTCHLITE 9810 Reflective Material Multipurpose Tape sold by MinnesotaMining and Manufacturing Co. (“3M”), of Saint Paul, Minn.

In one embodiment of the invention, the spherical pivot 220, mirror 230and/or the control arm 180 includes one or more fiducial markers. In analternative embodiment of the invention, the one or more fiducialmarkers are configured to be locatable by a remote positioning system aswell as imageable using one or more imaging modalities. In one suchembodiment, the outer surface of the eye-contact member is configured tobe light reflective, such as discussed above. The fiducial markers arestill advantageously locatable using one or more imaging modalities(e.g., MR, CT, or other imaging system providing 3D or other internalimages within a subject) as well as also being locatable external to thesubject, such as by using a remote camera or like component of anoptical or other positioning system, e.g., that is coupled to animage-guided workstation. In one embodiment, this permits automaticregistration of the actual location of the subject's eye (e.g., usingcameras to locate the light reflective fiducial markers) to pretreatmentimages of the system on which additional imageable fiducial markers arepositioned. This eliminates the need to register the eye of the subjectby inserting an optically-locatable positioning control arm onto thecontact device, and eliminates the need for other absolute positionreference, because the fiducial markers themselves are opticallylocatable and registerable to known locations on pretreatment images ofthe system.

Control arm 180 may be coupled to an image-guided workstation orplatform (not shown). In this embodiment, control arm 180 includes anend that is sized and shaped to permit being coupled to spherical pivot220. The control arm 180 includes, in this embodiment, a plurality offiducial markers 520, 522, 524, 526, 528, 530 that are locatable by acamera or other like device of the optical positioning system. Thefiducial markers 520, 522, 524, 526, 528, 530 on the control arm 180 arepositioned in a known spatial relationship to each other and to the tipof the control arm 180. By recognizing the locations of the fiducialmarkers, the optical positioning system is capable of computing thelocation of the control arm tip, which is in a known spatialrelationship with the configuration of the fiducial markers. Thispermits the control arm 180 to be used in conjunction with the opticalpositioning system to register the eye of the subject and to furtherplan and/or perform the treatment procedure using an image-guidedworkstation. An image guided treatment computer workstation, which iscapable of displaying previously acquired and loaded pretreatment imagesof a the system. The optical positioning system connected to theworkstation includes an infrared light (or other energy source) thatprovides light that is reflected from the reflective fiducial markers.This permits the reflective fiducial markers on the control arm 180 tobe located and recognized by the cameras.

Pattern Detection

FIGS. 47B1 to 47I schematically illustrate a eye-guide device for use ina eye stabilizing system having aspects of the invention, and havingpatterned fiducials, and a method of determining orientation by imagerecognition. In the exemplary embodiment shown, a pattern of highlyreflective fiducials is mounted to the device. In the example shown thisis a triangular three-fiducial pattern (4), comprising fiducial 1 (oncenter bar 190) and fiducials 2 and 3 (on lens 120), although otherpatterns may be used. For example, the fiducials may have a surfaceincluding an adhesive-backed light-reflective tape, such as SCOTCHLITE9810 Reflective Material Multipurpose Tape sold by Minnesota Mining andManufacturing Co. (“3M”), of Saint Paul, Minn. Likewise, other methodsof applying or forming a reflective surface may be used, such asreflective ink compositions, and the like.

Placement of the fiducials may conveniently be chosen such that theyform right triangle (90-45-45) when eye-guide is inalignment—perpendicular and coaxial to system center (see FIG. 2B). Fortwo lens fiducials, angle of 45 degrees is preferred as a bestcompromise for horizontal and vertical sensitivity during measurement(i.e., if for example selected angle is 60 degrees it would providegreater horizontal sensitivity, but less vertical). Also, lens fiducialsare surrounded by the dark area in order to provide for easierdetection.

By virtue of the center pivot 220 the center fiducial 250 can move inhorizontal and vertical direction in relationship to lens fiducials.That movement causes triangle relationship of the angles to change,which provides feedback of the alignment position, and hence thepatient's eye.

Reference is made to the description above with respect to the imagingsystem pattern recognition functions, illustrated also in FIGS. 34-35.In summary, the fiducials as illuminated by lights 405 provide ahigh-contrast image to axial camera 401 Computer processor 501 may beprogrammed by suitable software to process the electronic image signalsto delineate the image regions corresponding to the fiducials (usingknown image processing algorithms, such as contrast enhancement,filtering, intensity thresholds, edge recognition, and the like). Theprocessor can then define a center of mass for each fiducial image, andlocate the corresponding points in a coordinate frame of reference, soas to create a mathematical representation of the fiducial pattern fromthe camera perspective. The mathematical representation then permitscalculation of relevant angles and dimensions, and so derive eye-guideposition and orientation information. Note that scaling information canbe used to derive Z axis distance information, alternatively oradditionally to the off-axis camera 402 described with respect to FIGS.3A,B. The process can be repeated from sequential camera images at anyselected position update rate (e.g., about 1 to 50 Hz) to providecontinuing position and motion data.

Once fiducials are recognized, and triangle angles and leg lengthscalculated, the processor 501 may provide feedback (e.g., via displayimages) to the user indicating which direction to move the eye-guide inorder to have it aligned. All three angles and their spatialrelationship may be considered in order to provide feedback to the user,for people it is easier to understand, and react to, one variable perdirection (i.e. up/down for vertical, and left/right for horizontal),lens fiducial angles are represented as a ratio to the user—A2/A1. Thisgives only one number for direction of movement. For example, in alignedcondition ratio would be one because 45/45=1; if mirror is tilted atsome angle to the right ratio might be 48/52=0.9231, etc.

In FIG. 47C the angles are identified as a, b and c, where a is theangle of the center fiducial 250 with respect to the lens fiducials.Angles b and c are the left hand and right hand angles. Angles a, b, andc determined by fiducial image recognition. Leg lengths l1, l2 and l3may be scaled to confirm Z position. A pattern height h (or width) mayalso be defined from detected data representing the distance betweenfiducial 1 and a line joining fiducials 2 and 3. Similarly, patternwidths may be defined (w1, w2). It should be understood that the samedetected image data may be expressed and organized as a number ofalternative sets of geometric parameters as steps in calculations,without departing from the spirit of the invention.

FIGS. 47B1 and 47B2 illustrate the effect of tilt of eye-guide 110, therotation of the center-post 222 about pivot 220, causing fiducial 1 tomove in the opposite direction to lens 120. Tilt may be horizontal,vertical or combinations of these. Note that the effect of tilt is tocause a ±change in the distance between fiducial 1 and the lensfiducials 2 and 3, depending on direction of tilt (compare h1 un-tiltedwith h2 tilted).

Six cases are illustrated in FIGS. 47D-I:

FIG. 47D shows the eye-guide aligned with geometric axis, where a=90deg.; b=45 deg.; and c=45 deg. This corresponds to the left-hand imageof FIG. 20H.

FIG. 47E shows the eye-guide positioned upward (post tilted up relativeto lens), but aligned horizontally, where a<90 deg.; and b=c>45 deg.This corresponds to a tilt in which height h is increased.

FIG. 47F shows eye-guide positioned downward (post tilted down), butaligned horizontally, where a>90 deg.; and b=c<45 deg. This correspondsto a tilt in which height h is decreased, as shown in the right-handimage of FIG. 20H.

FIG. 47G shows eye-guide positioned to the right (post tilted right),aligned vertically, where a<90 deg.; b>45 deg.; and c<45 deg. Thiscorresponds to a tilt in which width w1 is decreased and width w2 isincreased.

FIG. 47H shows eye-guide positioned to the left (post tilted left),aligned vertically, where a<90 deg.; b<45 deg.; and c>45 deg. Thiscorresponds to a tilt in which width w2 is decreased and width w1 isincreased.

FIG. 47I shows general case: eye-guide positioned off-center verticallyand horizontally, where a≠90 deg.; and b≠c, specific angles valuesdetermine orientation This corresponds to a case in which each of h, w1and w2 differ from the nominal values as shown in the aligned case ofFIG. 20B.

Note that the methodology described with respect to FIG. 47A-I may beapplied to fiducial patterns distributed in different structuralelements of eye-guide 110. FIGS. 48A-F illustrate an eye-guide device110 having a pattern of fiducials, the guide for use in a eyestabilizing system having aspects of the invention, shown in contactwith an eye and depicting the method of determining alignment. In thisexample, the fiducials 2, 3 are on an extended cross bar 190 andfiducial 1 is on an elevated center-post 222, so as to create a linearpattern when aligned. As shown, the eye-guide does not necessarily havea mirror surface, but includes a plurality of fiducials, e.g., 3fiducials having a highly reflective material (e.g., “Scotchbright”),one at the top of the center post (1), and two on the support arm oneither side of the center post (2, 3). The fiducial arrangement shownpermits a transparent lens 120 to be free of fiducials, which promotesdigital image-recognition of the limbus. In addition the eye-guide maybe tracked by camera image processing without a collimated and alignedlight source (e.g., a laser), and may be tracked under simple lighting,such as LEDs positioned adjacent the eye.

In the case of alignment with the system coordinate axis (see FIG. 48D,compare with FIG. 47D), the angles b and c=0°, the angle a=180° and thelengths l2=l3. Note the effect of the horizontal tilt of center-post 222(FIGS. 44E-F) is to render the lengths l2 and l3 unequal, even when theeye-guide center pivot 220 intersects the system axis 2810. In thesimilar case of vertical tilt (not shown), the angles a,b are not zero.

FIGS. 48 B-D show three perspective views, each with a differentorientation to the viewpoint, which can be a camera. View B is angledsubstantially, so that the fiducials 1-3 form a triangular pattern 4,which may be measured by image recognition methods. View C is angledless and presents a correspondingly smaller triangular pattern. View Dis aligned with the view point, and show a straight line arrangement,with equal right (2-1) and left (3-1) legs between fiducials. Note thatthe aligned pattern of View D is very easy for a operator to recognizevisually, either directly or as displayed on a user interface.

FIGS. 48 E-F illustrate that rotation of the center post 222 about pivot220 will result in a shift of the center fiducial 1 (in X or Y or both),even when the eye-guide support arm 190 is perpendicular to the viewingaxis.

Example of Alignment Method

As shown if FIGS. 33-37, the imaging system 410 has a known position andorientation relative to X-ray source positioning system 115 ofradiotherapy system 10 in a global coordinate system. In preferredembodiments, the imaging system is supported to be movable by positioner115. For example, as shown in FIGS. 3B and 5, imaging system 410 may bemounted to imaging support 412, which in turn may be mounted to move inconcert with XYZ stage 416 while remaining independent of Φ actuator 413and θ actuator 414.

In an example method using particular device and sub-method embodimentsdescribed in detail herein (e.g., as shown FIGS. 39-40 and 48 usingmethods shown in FIGS. 43A-E), the method may include all or some of thefollowing:

(a) Initially, the patient is positioned in head restraint 160 of system10, with eye guide 110 engaged and lens 120 centered on limbus 26.

(b) The imaging system 410 is moved into a position (e.g., by positioner115 X, Y and/or Z motion) where the retro-reflecting fiducials 1-3 ofthe I-Guide 110 can be viewed by the imaging system 410 (e.g., bycameras 401-402 in FIGS. 34-35 communicating with a system processor 501and an operator display 403).

(c) As image data from the fiducials is processed into spatialinformation (see flowchart FIGS. 50-51, described further herein), thepositioner 115 may be configured so as to auto-align (or manually) tothe center of the I-Guide crown in X and Y (center fiducial 2 in FIGS.48A-F).

(d) The operator then adjusts the I-Guide angle until it is orientedalong the system axis as shown in FIG. 43C, for example by rotationabout eye-guide pivot 220 by adjustment of eye-guide positioner 600along X′, Y′ and/or Z′ axes. Further auto-alignment of the X and Y axesof positioner 115 brings the eyeguide axis into co-linearity with thesystem Z axis. In this configuration the eye geometric axis 2810 iscollinear with the Z axis of positioner 115.

(e) The positioner 115 may then be offset in X and Y to shift the systemZ axis from alignment with geometric axis 2810 to align with an off-settreatment axis 2820 (X₀, Y₀ in FIG. 43E). In one treatment plan example,this is a shift of 1.16 mm temporally (may be ±X depending on if theleft or right eye is being treated) and −0.47 mm caudally (−Y), as shownin FIG. 43D. Note that this shift may alternatively be done before orafter the Z₀ and Φ₀ adjustments.

(f) With the eye-guide 110 and positioner 115 aligned as described, thepositioner 115 is moved axially along the Z axis until it reaches theselected treatment position (Z₀ in FIG. 43E), and the x-ray source 112is rotated about the Φ axis to the selected beam angle (Φ₀ in FIG. 43E).In this configuration, the spot of laser beacon 1410 is directed toappear on beam entry spot 311 (see FIGS. 34 and 36). The operator mayconfirm beam position and clearance of the beam from the limbus 26 byvisual display via cameras 401-402, and the system 10 may confirmalignment by image processing and recognition of both laser beacon andlimbus.

(g) (i) In a preferred treatment practice, the system is maintained inthis configuration in four degrees of freedom (X₀, Y₀, Z₀, Φ₀), andfurther stereotactic re-positioning of the X-ray source assembly 420 isconfined to rotation about the θ axis of positioner 115.

(ii) Note that where the treatment axis 2820 at (X₀, Y₀) intersects aretina-surface target center 318 (e.g., center of the macula) and thecombination of (Z₀, Φ₀) aims the beam path 1400 to intersect thetreatment axis 2820 at the target center, subsequent rotation about theθ axis causes the stereotactic beam paths to describe a cone with theapex at the target center 318. The combination of (Z₀, Φ₀) may also beselected to provide clearance from limbus 26 and eye lens 36, so as tohave sclera entry points 311 _(i) distributed spaced-apart in a roughlycircular arc outside but adjacent to limbus 26 (see FIG. 30A).

(iii) For example, the first treatment beam may be at an angle ofθ=180°. For convenience, a θ angle of 180 degrees (referenced from 0°north) may be referred to as the 6 o'clock position (beam 1 at θ₁ inFIG. 43E). Other treatment positions may be selected by adjusting the θangle e.g., beam 2 at θ₂ and beam 3 at θ₃, at roughly the “5 o'clock”and “6 o'clock positions” (θ≈150° and 210°, respectively).

(iv) Alternatively or in combination, adjustment of other DOF may beperformed, targeting beam 1400 to suit an alternative treatment plan.

Example of Image-Based Eye and Eye-Guide Measurements.

The exemplary embodiment of the imaging system 410 may be configured toacquire data at a selected rate for each camera, and typically theprocessor processes and calculates data at a selected update rate, e.g.about 10-50 HZ. In one example, a set of direct measurements are made atan update rate of 30 Hz, and used to calculate an additional set ofinferred measurements as data is updated.

As shown in the eye-guide example shown in FIGS. 48A-F, the directmeasurements are performed automatically using image processing andpattern recognition software on a frame-by-frame basis from camera videoinput signals, and include:

1 Eye Limbus Center X-Y Position.

-   -   Viewed from the on-axis main system camera 401.    -   Locates anatomical transition between the dark of the iris and        light of the sclera (limbus margin 26 in FIG. 30A).    -   Defined by center of mass of the best fit circle using limbus        detection software

2 Eye-Guide 110 Yoke X-Y Position (Yoke or Tie Rode 190 in FIG. 48).

-   -   Viewed from the main system camera 401.    -   Locates 2 fiducials on the tie rod (fiducials 2 and 3 in FIG.        48)    -   Defined by the center of mass between 2 fiducials (Yoke)    -   Note that the relative positions of yoke 190 and crown

3 Eye-Guide 110 Crown X-Y Position.

-   -   Viewed from the main system camera 401.    -   Uses infrared light from the IR LED bank of lights 406, close to        axis of camera 401.    -   Locates the fiducial on the tip of the Eye-guide 110 (fiducial 1        in FIG. 48).    -   Defined by the center of mass of the fiducial (crown)

4 Eye-Guide 110 Yoke 190 Z Position.

-   -   Viewed from the off axis range Z camera 402.    -   Defined by the center of mass between the 2 fiducials on the tie        rod (fiducials 2 and 3 in FIG. 48)

The calculated measurements are performed automatically using systemcomputer processors on a real-time basis as direct measurements areupdated, and include:

5 Base Lens 120 X-Y Position.

(a) This is a projected estimation of the center of the base lens 120approximately at the same plane of the limbus measurement. The inputsinclude measurements 2 and 3 (X-Y of yoke 190 and crown fiducial 1,respectively), which define an eye-guide longitudinal axis, which can beextrapolated from the known structural geometry of eye-guide 110 todetermine the lens X-Y.

(b) Note that the relative detected X-Y positions of yoke 190 and crownfiducial 1 also define an eye-guide axis angle relative to system 10coordinates (analogous to eye-guide 110 “pitch and yaw”, designated hereas eye-guide (I)).

(c) Note also that the relative detected vertical positions of fiducials2 and 3 on yoke 190 define an eye-guide angle in the system X-Y plane(analogous to eye-guide 110 “roll”, described here as eye-guide θ). Incertain embodiments, this may be largely be controlled by the support ofhead-chin restraints 160 and eye-guide positioner 600, and the eye-guideθ value may be small or negligible.

6 Limbus-to-Lens Coupling.

-   -   This is a functional measure based on the amount of relative        movement between the base lens 120 X-Y position and the limbus        26 X-Y position.    -   Relative motion that exceeds a threshold value (e.g., 500        microns) may be interpreted as an indication that the base lens        120 has shifted from its original location at eye alignment or        has become decoupled.

7 Retinal Target 318 X-Y-Z Position.

-   -   This computation involves all detected motion parameters so as        to estimate the related motion at the back of the eye, inferred        as motion of the retinal target 318. (See retinal motion        tracking embodiments as described further in co-invented        Application No. 61/093,092 filed Aug. 29, 2008, which is        incorporated by reference).    -   Gating algorithms and criteria are based on these calculations        (See X-ray source gating embodiments as describe further in        Application No. 61/093,092).

Note the eye alignment method flowchart and geometric diagrams of FIGS.43A-E in regard to examples of the use of the measurement as describedabove by the system 10 computer processors 501 (via suitable software)and displays 503 a,b: For example:

-   -   Measurements 1, 5 and 6 (relative position of eye-guide lens 120        and limbus 26) may be displayed to assist a physician in        placement of eye-guide 110 as shown in FIG. 43B as centered on        the limbus, and used to automatically confirm eye-guide        placement accuracy.    -   Measurements 2, 3 and 5a,b (eye-guide angle and eye-guide X-Y)        may be used to guide and/or automatically drive the motion M(x,        y, Φ, θ) of FIG. 43C(1) to align the eye geometric axis 2810        coaxially with system Z axis (relative values eye-guide X, Y, Φ,        θ versus system 10 coordinates and Z axis become zero).    -   Measurements 2, 3 and 5 may be used to confirm accuracy of the        X-Y shift of positioning system 115 from geometric axis 2810 to        treatment axis 2820, as shown in FIG. 43D.    -   Measurement 4 may be used to confirm accuracy of positioning        system 115 movement to the treatment Z position (Z₀) as shown in        FIG. 43E.    -   All the above measurements may be used to track eye position and        retinal position on a real-time basis during treatment.

Example of Eye-Guide Data Extraction and Eye Motion

FIGS. 49 through 54 pertain to measurements of eye motion of patientswho are engaged by an eye alignment, stabilization and tracking systemhaving aspects of the invention, such as are depicted in FIGS. 39-48.These aspects also include mechanisms and methods for assuring that anyresidual motion of the stabilized eye does not prevent radiotherapy tobe effectuated with dosage distribution adjacent a target region remainswithin planned parameters. In should be understood that the imaging andmeasurement methodology described in this section are exemplary, andother methods and devices having aspects of the invention are describedherein and in the applications incorporated by reference.

FIGS. 49A-E are plots showing eye movements experimentally measured withan embodiment of a system for controllably positioning and/orstabilizing the eye of a subject. In the this particular embodiment, thedata was acquired using three video cameras mounted on an embodiment eyestabilization and tracking system having aspects of the invention. Notethat the particular camera/imaging configuration used in the exampleillustrates one of a range of alternative embodiments comprising camerasand/or other sensor configured for acquiring motion data of the natureshown. For example, FIGS. 3A-B illustrate and imaging system employingtwo cameras, capable of acquiring comparable eye motion data. In theexample of FIGS. 49A-E, for each patient, video from each camera wasprocessed, frame by frame, in order to extract desired data. The cameraswere configured as follows:

-   -   “PSD camera”, also referred to as “fine angle data”. Coaxial        laser beam is reflected from the eye guide's mirror and detected        by the camera. Although enabling high resolution data to be        extracted, this setup can only collect data within very limited        range of +/−1.25 deg.    -   “Central camera”—the eye-guide fiducial data; camera is mounted        perpendicular to patient's eye and can view eye guide's lens and        mirror, as well as anatomic data such as limbus position.    -   “Z-range” camera—distance data; camera is able to see eye-guide        mirror but is mounted to the side of central axis. eye guide's,        and hence patient's fore and aft movement (Z axis) is accurately        easily detected.

Fine Angle Data

PSD camera is set up such that reflected laser beam is visible as awhite (bright) area contrasted on the dark background in the cameraview. Every frame from the video is individually extracted, and usingcustom algorithm and software, location and centroid of the laser areais determined. Centroid data is expressed in (x,y) pixel coordinates andusing predetermined conversion factor translated to angle in X directionand angle in Y direction. Conversion factor is (pre)determined based onset-up and calibration data. Since knowing patient's head movementduring the treatment was desired (i.e. relative movement) each angle inX and Y direction was subtracted from the very first recorded datapoint.

Fiducial Data

Using custom algorithm and software each frame from the central camera'svideo is extracted, and fiducials on Eye guide's lens (2) and mirror (1)are detected. Center of each fiducial is expressed in (x,y) pixelcoordinates. By design fiducials form a triangle, therefore it ispossible to calculate angles within a ‘fiducial’ triangle. Angle formedat center of the eye-guide mirror is used for vertical determination (Yangle), and ratio of angles formed by fiducials on the lens is used forhorizontal determination (X angle). Relative motion data was desired soeach acquired data set was subtracted from the first data point. Duringthe study, the fiducial location differed slightly on each lens, withouteffecting the method. Fine X and Y angles were paired to X and Yfiducials and correlation factor was determined per each patient's dataset. Correlation factor was determined by using line equation y=ax+b,where y is fiducial data, a is slope, x is fine angle data, and b isoffset. Variables a and b were determined using few points from data set(in future whole set should be interrogated).

Distance Data

Laser spot reflection on the eye-guide's mirror, as seen by set“Z-range” camera was used to determine distance data. For each videoframe, center of laser spot was detected using custom algorithm andsoftware (see further description of measurements under caption “Exampleof image-based eye and eye-guide measurements.”. Note that in additionto the image-based methods described, range data may be obtained byultrasound or other reflected-signal techniques. Using predeterminedcalibration and correlation factors, each detected location wasconverted from pixels to millimeters. Other image data may be used inlieu of laser spot, such as light impinging on eye-guide 110 from an LEDlights source (e.g., visible or IR).

The measurements shown in FIGS. 49A-E are from a typical patient who wastolerating the procedure well for the administered period of about 300seconds (5 min.), and are as follows:

-   -   A. Horizontal X motion of the eye-guide and the limbus, plotted        together to show relative motion of these.    -   B. Vertical Y motion of the eye-guide and the limbus, plotted        together to show relative motion of these.    -   C. Horizontal X motion of the eye-guide mirror due to angular        deflection about the pivot.    -   D. Vertical Y motion of the eye-guide mirror due to angular        deflection about the pivot.    -   E. Z motion of the eye-guide due to motion of the eye        posteriorly.

It may be seen that each parameter includes movements of on the order of1 mm or less, and most less than 0.5 mm, over a substantial period of 5minutes without any realignment procedures.

FIGS. 50 and 51A-B are flowcharts illustrating data acquisition andprocessing used in this example, and are self-explanatory to one ofordinary skill in the art. It should be understood that the algorithmsand methods depicted are merely an example to demonstrate thefunctionality of one embodiment of the system, and alternative oradditional particulars and sub-methods may be included without departingfrom the spirit of the invention.

The flowchart of FIG. 50 (on two sheets) is a summary of the fiducialdetection algorithm employed in obtaining the data of FIG. 49. The inputto the method is a video signal captured by system cameras. The dataflow is a loop which processes each frame of video data, preferably on areal-time basis as each frame is captured. Alternative methods canselect particular frames for data computation (e.g., in a timed sequenceto support a desired data update rate), for example where a greaterframe rate is desired for a user visual display than is desired for datacomputation. As may be seen, the output from the method are particularcomputed values, which in this example are depicted as being written ascorrelated with the particular video frame to memory media, indicated as“save file”. It is to be understood that these output values mayadditionally or alternatively be directly accessed by system electronicprocessors for further display, computation or control functions.

The flowcharts of FIGS. 51A and 51B depict further processing andconversion steps based on raw date obtained from the video frames, suchas in the process of FIG. 50.

Extrapolation of Eye Movement to Retinal Movement, and Dosage Mapping

Tracking of eye motion as described above may be correlated with avirtual eye model having aspects of the invention, such as are describedherein to assess movement of particular eye anatomy during radiotherapytreatment, for example, the movement of a retinal target region relativeto the path of an X-ray beam during treatment. Such anatomical movementmay in turn be used to assess actual absorbed radiation dosage and itsdistribution in relation to a planned radiotherapy treatment.

It has been demonstrated the low levels of suction (e.g., 25-50 mm Hg)are sufficient to provide reliable coupling of the eye-guide 110 to theeye, so as to maintain the eye guide at a selected position (e.g., withlens 120 centered on limbus 26 in contact with cornea 12 and sclera 17).

However, eye motion may still occur on the scale of a fraction of amillimeter to a few millimeters even where the eye-guide 110 andeye-guide support assembly are substantially rigid and coupled to theeye, and where chin-head restraint assembly 160 provides firm headsupport (e.g., generally firm chin and forehead members 171, 172 and asnug head fastener 161). Sources of residual voluntary or involuntaryeye movement include: (a) the eye is movably mounted in the skull, andmay be moved within the orbit and adjacent soft tissue, such as by theeye muscles or head motion; and (b) the skin and soft tissue coveringthe skull, face and chin is generally loose and free to move withinlimits over the underlying boney support, and such motion may permit insmall head movement, which then applies rotational and/or translationalforces to the eye, as the eye tends to follow the head motion.

It should be understood that the certain eye stabilization methods anddevices having aspects of the invention may omit more aggressivemeasures to eliminate eye motion, such as temporary eye paralysis,high-suction contact eye-holders and/or rigid and forceful mechanicalclamping of the skull, or the like. Less aggressive stabilizationmeasures can lower treatment costs, improve patient acceptance, andreduce treatment time. Trade-offs in patient comfort, convenience, andcost can be made which favor tolerating and/or compensating for aselected modest level of eye position/orientation change duringtreatment versus absolute eye motion prevention.

Alternative retina target tracking, dosage mapping and compensationmethod and device embodiments having aspects of the invention providesafe dosage control where a residual level of eye motion is presentduring treatment. In addition, the methods and device embodimentsprovide a “fail-safe” functionality for treatment procedures which havelow levels of eye motion.

FIGS. 52-54 graphically illustrate the effect of particular eye motionsof an eye engaged by an eye-stabilization system having aspects of theinvention on motion of the retinal, including a treatment target (e.g.,the macula) and a sensitive structure (e.g., the optic disk). In eachcase a radiotherapy beam is targeted on a region encompassing at least aportion of the macula, and the views show the beam initially aligned onthe target, and show the effect of a particular movement away fromalignment. The structure of the assembly 117 is essentially similar tothat shown in FIGS. 41-42.

FIGS. 52A-B are two views from above of an eye-guide included in a eyestabilizing system having aspects of the invention, shown in contactwith an eye during X-ray treatment, illustrating the effect on retinalposition of motion of the eye in the system Z direction. In this case, aposterior Z movement (see FIG. 49E) can be seen that the eye motiontranslates the retina along the Z axis without components of motion ofthe retina in the X or Y axis. However, the eye motion does result in arelative motion of the beam spot on the retina due to the angledalignment of the beam with the retina. In this illustration, thebeamspot moves relatively in the X direction as shown, for a beam angledfrom the opposite direction.

It will be apparent that the direction of relative motion of thebeamspot is dependent on the X-ray beam orientation relative to the Zaxis (see angles Φ and θ in FIG. 37), and in the general case of anarbitrary angle, a motion of the eye in the Z direction will result inboth X and Y components of the relative motion of the beam-spot inrelation to the planned target. It will also be apparent that the scaleof such relative motion is dependent on the angle Φ of the beam with thetreatment axis, a small angle Φ resulting in a relatively small movementof the beam-spot in relation to eye motion on the Z axis. In a preferredembodiment, angle Φ is kept constant during stereotactic re-positioning,with angle Θ changed for each beam application.

FIGS. 53A-B are two views from above of an eye-guide in contact with aneye during X-ray treatment, illustrating the effect on retinal positionof motion of the eye angularly about the pivot of the eye guide. In thiscase, the eye and lens are pivoted through a small angular change dα(see FIGS. 49 C-D). Note that although the pivot is assumed here to befixed, the eye motion is both in translation and in angular orientation.This can be seen to result in a motion both of the eye-guide lensfiducials (shown in the X direction, but generally in both X and Y), andin a larger motion of the retinal target in the same direction, due tothe longer moment arm pivot-to-retina relative to the shorter moment armpivot-to-lens.

FIGS. 54A-B are a comparison between the lateral illustration of FIG.52B (reproduced as FIG. 54A) and two frontal schematic views of aphantom eye, wherein FIG. 54B _(L) shows frontal projection of lensmovement, and FIG. 54B _(R) shows frontal projection of correspondingretinal movement. Note that FIG. 54B _(L) shows a relatively smallmovement lens fiducials relative to the movement of the eye body.

FIG. 54B _(R) has a projection of retinal target geometry, as show moreclearly in attached detail view, and shows retina beamspot b. Note thatthe motion of the retina in this example moves the optic disk (od) intothe path of beamspot b, and move the macula out of the treatmentbeamspot, both undesired effects with respect to the exemplary treatmentplan.

FIG. 54C is a flow chart illustrating an exemplary planning methodincluding determining a safe or allowable eye movement threshold to bepermitted during treatment. The method may comprise the steps of:

(a) Aligning an ocular axis (e.g., eye geometric axis 2810) withtreatment system reference axis (e.g., Z axis of positioner 115) insystem External Coordinate System (ECS).

(b) Determining macula and optic nerve coordinates in ECS, inputs mayinclude (1) Direct measurement or visualization of patient ocularanatomy, such as OCT, CT and fundus imagery, or the like; and (2)Application of a predetermined eye model (e.g., see FIGS. 19-20).

(c) Establishing treatment beam axes in ECS (e.g., see FIG. 43E).

(d) Determining maximum safe eye movement and duration for each axis(FIG. 54D).

(e) Output is a Treatment plan with beam-source settings, irradiationtime, and allowed eye movement for each treatment axis.

FIG. 54D, Views (1)-(3) illustrate the relation of retinal motion toradiation dose distribution. Views (1) and (2) are schematicrepresentations of anatomy of retinal surface 1435 including optic diskcenter 32, optic disk edge 32 a, macula center 318 (approximately thefovea) and the retinal pole or intersection of geometric axis 2810. Alsoshown are one or more treatment beams 1400, impinging (e.g.,stereotactically) to form a beamspot on or adjacent the macula center318. In View (1) the distance in the retinal X-Y plane between maculacenter 318 and optic disk center 32 is indicated as L_(M). Views (1) and(2) represent the relative geometry at different time instances duringthe course of treatment.

In View (1), indicated as time t=0 (although this need not be thebeginning of treatment), the one or more beams are aligned according toan exemplary treatment plan to center (in combination for plural beams)on macula 318, to that the distance R between beamspot center 1441 andoptic disk 32 is the same as L_(M). (Rt=₀=LM)

In View (2), indicated as time t=1 (where 1 represents an arbitrary timeinterval), eye motion has occurred having the effect of moving theretina by increments dx and dy in the retinal X-Y plane. Note from FIGS.52 through 54B that motion of the eye in the Z direction and angular eyemotion can produce consequent X and Y motion of the retina in theExternal Coordinate System. The beamspot 1441 has moved relative to theoptic nerve 32, so that distance R at (t=1) is no longer equal to L_(M).In the example shown, R (to that the distance R between beamspot center1441 and optic disk 32 is the same (e.g., Rt=₁<LM).

View (3), indicated is a plot showing the effect of retinal motion ofthe cumulative distribution of radiation dose at the retina, where thevertical axis is increasing dose (either at a given time point or atotal for the treatment), and the horizontal axis is increasing distancefrom macula center 318 toward optic disk center 32. The bold curves,solid and dashed, show the maximum allowable threshold dose and planneddose, for each point, for the entire treatment. the light curves showthe cumulative dose to time t=1 for the planned treatment (dashed) andthe treatment accounting for retinal motion (solid). As may be seen inthis example, a low threshold is permissible at the optic disk, and inthe case shown, at t=1 this threshold has been exceeded, triggering asystem response, such as gating of radiation emission.

The total dose of radiation to tissue may be assessed either at end oftreatment or at any point during treatment, or both. The total dosebetween two time points at any point within ocular anatomy may berepresented by a summation or integral of the dose received during theincluded time increments. For example, where R_(t) represents thedistance from the beamspot center to the selected tissue location anytime t, the Total Dose ∫_(0 to t)D_(R)(Rt)dt, where D_(R) is the timeincrement fractional dose at the tissue location (which is a function ofbeamspot location Rt). Alternative mathematical representations may beemployed without departing from the spirit of the invention.

Real-Time Retinal Motion Dose Mapping, and X-Ray SourceGating/Realignment.

The co-invention U.S. Application No. 61/093,092 filed Aug. 29, 2008 andNo. 61/076,128 filed Jun. 26, 2008 (each of which is incorporated byreference) provide, among other things, detailed description of methodsand devices having aspects of the invention for:

(a) extrapolating measured eye motion to provide a real-time signal ofthe motion of a retinal target (or other ocular structure);

(b) methods for real-time summation of radiation dose distribution to atreatment target and to tissues adjacent the radiation beam path basedon measured eye motion;

(c) methods and trigger algorithms for gating (interrupting) treatmentradiation upon threshold departures of dose distribution from plannedtreatment; and

(d) methods and devices for re-orienting a radiation source (e.g., X-raybeam collimator) to compensate for measured eye motion so as to maintainthe beam substantially on target.

Method and device embodiments include combinations of these aspects withthe methods and devices for radiotherapy treatment and planningdescribed in detail herein.

Combination and Radiodynamic Therapies

Radiotherapy device 10 can be used in combination with othertherapeutics for the eye. Radiotherapy can be used to limit the sideeffects of other treatments or can work synergistically with othertherapies. For example, radiotherapy can be applied to laser burns onthe retina or to implants or surgery on the anterior region of the eye.Radiotherapy can be combined with one or more pharmaceutical, medicaltreatments, and/or photodynamic treatments or agents. As used herein,“photodynamic agents” are intended to have their plain and ordinarymeaning, which includes, without limitation, agents that react to lightand agents that sensitize a tissue to the effects of light. For example,radiotherapy can be used in conjunction with anti-VEGF treatment, VEGFreceptors, steroids, anti-inflammatory compounds, DNA binding molecules,oxygen radical forming therapies, oxygen carrying molecules, porphyrynmolecules/therapies, gadolinium, particulate based formulations,oncologic chemotherapies, heat therapies, ultrasound therapies, andlaser therapies. See for example, Small, W. Jr, ed.; “Combining TargetedBiological Agents with Radiotherapy” Demos Med. Pub., New York 2008,which is incorporated by reference.

In some embodiments, radiosensitizers and/or radioprotectors can becombined with treatment to decrease or increase the effects ofradiotherapy, as discussed in Thomas, et al., Radiation ModifiersTreatment Overview and Future Investigations, Hematol. Oncol. Clin. N.Am. 20 (2006) 119-139; Senan, et al., Design of Clinical Trials ofRadiation Combined with Antiangiogenic Therapy, Oncologist 12 (2007)465-477; the entirety of both these articles are hereby incorporatedherein by reference. Some embodiments include radiotherapy with thefollowing radiosensitizers and/or treatments: 5-fluorouracil,fluorinated pyrimidine antimetabolite, anti-S phase cytotoxin,5-fluorouridine triphosphate, 2-deoxyfluorouridine monophosphate(Fd-UMP), and 2-deoxyfluorouridine triphosphate capecitabine, platinumanalogues such as cisplatin and carboplatin, fluoropyrimidine,gemcitabine, antimetabolites, taxanes, docetaxel, topoisomerase Iinhibitors, Irinotecan, cyclo-oxygenase-2 inhibitors, hypoxic cellradiosensitizers, antiangiogenic therapy, bevacizumab, recombinantmonoclonal antibody, ras mediation and epidermal growth factor receptor,tumor necrosis factor vector, adenoviral vector Egr-TNF (Ad5.Egr-TNF),and hyperthermia. In some embodiments, embodiments include radiotherapywith the following radioprotectors and/or treatments: amifostine,sucralfate, cytoprotective thiol, vitamins and antioxidants, vitamin C,tocopherol-monoglucoside, pentoxifylline, alpha-tocopherol,beta-carotene, and pilocarpine.

Other agents include complementary DNA, RNA, micro-RNA inhibitors (e.g.,U.S. Pat. No. 7,176,304, incorporated herein by reference), and SiRNA(e.g., see U.S. Pat. No. 7,148,342, incorporated herein by reference),all of which can be combined with radiation treatment. In someembodiments, these agents are provided with radiation treatment toimprove tumor control; treat inflammatory conditions; and prevent,reduce, limit, or stabilize angiogenesis.

Antiangiogenic Agents (AAs) aim to inhibit growth of new blood vessels.Bevacizumab is a humanized monoclonal antibody that acts by binding andneutralizing VEGF, which is a ligand with a central role in signalingpathways controlling blood vessel development. Findings suggest thatanti-VEGF therapy has a direct antivascular effect in human tissues. Seefor example U.S. Pat. No. 7,060,269 and US Published Application No.2005/0112126, each entitled “Anti-VEGF Antibodies”; each of which isincorporated by reference. In contrast, small molecule tyrosine kinaseinhibitors (TKIs) prevent activation of VEGFRs, thus inhibitingdownstream signaling pathways rather than binding to VEGF directly.Vascular damaging agents (VDAs) cause a rapid shutdown of establishedvasculature, leading to secondary tissue death. Themicrotubule-destabilizing agents, including combretastatins and ZD6126,and drugs related to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) aretwo main groups of VDAs. Mixed inhibitors, including agents such as EGFRinhibitors or neutralizing agents and cytotoxic anticancer agents canalso be used.

In one combination therapy method embodiment for AMD having aspects ofthe invention, advantageously at least one intravitreal injectiontreatment with an anti-VEGF antibody or antibody-derived agent such ase.g., ranibizumab or Lucentis® by Genentech may be administered to thetreated eye shortly before or close to the time of radiotherapytreatment with system 10 as described herein, such as by a treatment ofabout 5 Gy to about 35 Gy (preferably from about 10-25 Gy) absorbed in aretinal treatment region including the macular lesion (e.g., about 4 to6 mm diameter region centered approximately on the fovea). Preferably atleast a second anti-VEGF treatment is administered about 2-6 weeksfollowing the radiotherapy treatment. In an alternative combinationtherapy method embodiment, intravitreal injection treatments withbevacizumab (Avastin®) may be used.

Radiodynamic therapy refers to the combination of collimated x-rays witha concomitantly administered systemic therapy. As used herein, the term“radiodynamic agents” is intended to have its ordinary and plainmeaning, which includes, without limitation, agents that respond toradiation, such as x-rays, and agents that sensitize a tissue to theeffects of radiation. Similar to photodynamic therapy, a compound isadministered either systemically or into the vitreous; the region in theeye to be treated is then directly targeted with radiotherapy using theeye model described above. The targeted region can be preciselylocalized using the eye model and then radiation can be preciselyapplied to that region using the PORT system and virtual imaging systembased on ocular data. Beam sizes of about 1 mm or less can be used inradiodynamic therapy to treat ocular disorders if the target is drusenfor example. In other examples, the beam size is less than about 6 mm.

Other compounds that can increase the local efficacy of radiationtherapy are metallic nanoparticles, such as gold, silver, copper, orcombinations thereof. These particles can further be tagged withtargeting binding agents so that the nanoparticles can bind to targetson blood vessels or macrophages to target higher doses of radiation tospecific areas of the patient. For example, Carter et. al. (JournalPhysical Chemistry Letters, 111, 11622-11625, which is incorporated byreference) report improved and enhanced targeting using nanoparticles ofgold. They further report even further targeting with targeting agentscross-linked to the gold particles. These nanoparticles can be combinedwith highly localized radiotherapy during treatment.

Alternative Corneal Beam Entry Radiotherapy Methods and Devices

FIGS. 55A-D depict alternative method and device embodiments havingaspects of the invention, for retinal external-beam therapy, such astreatment employing orthovoltage X-rays, laser light of variouswavelengths, or the like. In an example shown, the irradiation step iscarried out by directing X-rays to penetrate the cornea at beam entry,then propagating to retinal target such as the macula (or otherposterior eye target). See for example, see co-invented application Ser.No. 11/879,901 filed Jul. 18, 2007, especially FIGS. 7B, 7C and 7E,which application is incorporated by reference. Multiple stereotacticbeams may be emitted so as to spread the surface dose over a relativelylarge portion of the cornea, so as to reduce local radiation intensityto the cornea and the lens, while concentrating dose on a retinal targetsuch as the macula (or other posterior eye target). In certainembodiments a small opening may be repositioned sequentially to providea sparse or low average intensity pattern on the cornea whileconcentrating dosage on a retinal target.

Alternatively or in combination, the X-ray dose may bemicro-fractionated, such as where the radiotherapy system comprises acollimator configured to emit a beam cross section with a plurality ofregions of maximal intensity that are disposed in a spaced-apartcheckered, speckled, or dotted arrangement, so as to providemicro-fractionated radiation application to both the cornea and lens,during beam propagation to the target area. See co-invented applicationSer. No. 12/100,398 filed Apr. 9, 2008, especially the description ofFIGS. 2 and 11G, which application is incorporated by reference (FIG.55F herein is a reproduction of FIG. 11G of '398).

X-Ray Beam Parameter Selection.

Note that the methods described above with respect to FIGS. 8 to 14 maybe repeated for a treatment plan having an alternative beam path to aretinal target tissue, such as a path intersecting the cornea 12 ratherthan the pars plana of the sclera 17. In this manner, in certainembodiments a maximum X-ray photon energy and a filtration thickness(filter 1423 in FIGS. 21 and 56A) may be selected to achieve a desiredsurface-to-target dose ratio (inverse of fractional dose to target)suited to a specific treatment plan. Likewise, the effect of a differenttissue path length (e.g., close to eye axial length), the dosagereceived by a pre-target structure such as the lens 36 (see FIG. 20,1412), or the dosage received by a post-target organ such as the brain(see FIG. 20, 1413), may each be modeled as exemplified in FIG. 12 andconsidered in this selection. For example, a treatment plan forcornea/lens beam passage may select a somewhat higher maximum keV photonenergy and/or a somewhat thicker filter material than a otherwisecomparable treatment plan for pars plana entry such as shown in FIG. 20,so as to achieve a relatively larger dose fraction absorbed at theretina (and conversely a smaller dose fraction absorbed at the corneaand lens).

Micro-Fractionated Beam.

FIG. 55C is a schematic diagram of a collimator 118 associated with anX-ray tube 112, the anode spot 1420 positioned a distance L1 fromcollimator exit aperture plane 1405, with is in turn offset a distanceL2 from the surface of cornea 12 of eye 30 (shown as planar eye modelsimilar to FIG. 21). Aperture plane 1405 includes a plurality of smallopenings 1405 a, which may be arranged in a random or in a geometricallyregular pattern. Preferably, the plurality of openings sparsely cover abeam exit area sized to produce a overall beam spot 1441 having patternof comparatively minute sub-spots 3090, upon propagation of beam 1400 toretinal surface 1435 (e.g. the macula). Beam spot 1441 may be circularin general shape, or may have another shape, such as oval, crescentshaped, elongate, polygonal or irregular.

Preferably, a combination of anode size 1420, collimator length L1,opening diameter 1405 a, and exit offset L2 (which may be zero) isselected so that the penumbra of each sub-spot 3090 is small in relationto the distance between sub-spots in the pattern of beam spot 1441(“matrix” portions 1441 a of the dotted pattern of beam spot 1441). Thispermits substantial areas of the corneal beam entry spot 311 to have lowX-ray dose intensity relative to the sub-spots 3090, and consequentreduced physiologic radiation effects. Similarly, intra-ocularstructures such as the lens 36 have substantial volumes within thediameter beam 1440 of reduced dose intensity.

In certain micro-fractionated embodiments, the anode size, thecollimator offset L2, and/or the anode-to-target distance (L0=L1+L2+L3)may optionally be different (e.g., smaller) than typically employed inthe uniform beam embodiments described in detail herein, or a differenttype of X-ray tube 112 may be selected. Filtering (such as filter 1423in FIG. 21) and/or maximum photon energy may be selected to accommodatediffering tissue path length L3 and/or to produce a selectedsurface-to-depth dose ratio suited to micro-fractionated corneal entrytargeting. The treatment planning methods having aspects of theinvention and described herein in detail may be used to selected theseparameters (see FIGS. 8-13 for example). Numerical simulation such asMonte Carlo simulation and radiographic phantom modeling as describedherein may be used to optimize and validate parameter selections.

The collimator-X-ray assembly 118-112 may be mounted and operated in themanner of X-ray source assembly 420 of radiotherapy system 10, as shownin FIGS. 33-37 and described in detail herein, the beam positioninggeometry in this exemplary embodiment being adapted to suit thetreatment plan and targeting method illustrated in FIGS. 55 A-D. In thisexample, the tissue path length is approximately the eye axial length(distance from cornea anterior center to retinal surface), with smallvariations due to beam orientation.

FIG. 55D is a cross-section of an eye 30 showing, the a plurality ofdifferent beam paths b1-b2 having different corneal entry points 311a-311 d, the beam paths being generally distinct when traversing cornea12 and lens 36, and converging to overlap at retina 1435, in thisexample covering a macular target region 318.

Method embodiments may include the administration, e.g. in eye-dropsprior to patient treatment, of a known ophthalmic mydriatic agent (e.g.,Paremyd, Mydriacyl, Cyclogyl, or the like.) to induce dilation of pupil25 to facilitate visualization and targeting of the retina, as shown inFIGS. 55A and D. A pharmacologically-dilated pupil in a typicalpopulation may range from about 7.0 mm to about 8.5 mm in diameter,although individuals vary considerably and older adults tend to havesomewhat less dilation. See for example, Yang Y. et al; “Pupil Locationunder Mesopic, Photopic, and Pharmacologically Dilated Conditions”;(2002) Investigative Ophthalmology and Visual Science 43:2508-2512,which is incorporated by reference. Alternatively or in combination, allor a portion of the beam 1440 may penetrate the iris 24.

FIG. 55A illustrates one embodiment of a micro-fractionated treatmentmethod. In this example, a plurality of beams (six beams b1-b6 areshown) are oriented so as to intersect the cornea near the edge of theiris at entry spots 311 a-311 f). For example, the collimator 118 may beoriented by positioning system 115 in FIG. 33-37). In this example, theentry spots 311 are space to avoid overlap with one another, and toleave a substantial area of the central cornea un-radiated (thearrangement need not be hexagonal, as shown). However alternativeembodiments may have overlapping and centrally targeted entry spots 311.The plurality of beams converge on retina 1435 at target region 318. Inaddition to the concentration due to stereotactic orientation, theindividual beam spot patterns 1441 may be rotated or slightly offset toone another, so as to approximate uniform radiation dose to targetregion 318 (e.g., disposed so that sub-spots 3090 only minimallyoverlap).

Although treatment axis 2820 is illustrated in FIG. 55D as beingsubstantially parallel to geometric axis 2810, in certain embodiments itmay be non-parallel. For example, for treatment of a macular target 318may have a treatment axis 2820 offset from the geometric axis by offset2850 defined by dx and dy in the retinal plane 1435. as shown in FIGS.55A and D In such a method, treatment beam axis 2820 may be defined at aslight angle to axis 2810, so that a conical stereotactic beam pattern(b1-b6) which has a cone base defined by entry spots (311 a-f) which arecentered symmetrically near the iris edge 25, while providing that thecone apex (beam intersection) is located at the center of off-set target318. As with other embodiments described herein, this arrangementpermits a single DOF rotational motion (e.g., by motion in θ by actuator414 in FIG. 37) to move the collimator 118 to each successive beam pathb1-b6.

Stereotactic Corneal Pattern of Narrow Beams.

FIGS. 56A-E depict alternative method and device embodiments havingaspects of the invention, for retinal external-beam radiotherapyemploying a plurality of narrow X-ray beams 1440 _(i) having astereotactic pattern 312 at point of entry into corneal tissue surface,focusing to define a concentrated dose distribution at a target region318 deep to the surface of the eye, such as a macular lesion. Thesurface pattern 312 and the target pattern 318 collectively define aplurality of linear stereotactic beam paths 1441 _(i) to which an X-raysource may be sequentially aligned.

FIG. 56A depicts an example of a collimator assembly modeled inassociation with a planar eye representation in the manner of FIG. 21,comprising X-ray tube 112 having a source anode 1420 positioned adjacentcollimator 118, in this example having a filter 1423 and a collimatorexit aperture 1405. In operation, the X-ray source and collimator 118may be positioned (such as by a robotic positioner 115) so as to emit anincremental beam along a beam path 1400, to intersect an incrementalcorneal entry spot 311 _(i), then propagating through eye tissue to anincremental retinal beam-spot 1441 _(i).

Attention is drawn to the description herein regarding the selectionamong alternative X-ray sources and tubes, such as shown in FIG. 33A-B.An embodiment such as shown in FIG. 56A may employ a comparatively smallanode spot size 1420 (e.g., a commercially available tube 112 having afixed anode and a variable-focus permitting selection from a range ofanode spot sizes). Along with anode size, the dimension of collimator118 (aperture 1405, and longitudinal distances L0, L1, and offset L2)may be selected to provide the desired dimensions of retinal beam spot1441 and penumbra 1442.

For example, in certain embodiments, the effective anode size 1420 andthe collimator aperture diameter 1405 may be of the same order ofmagnitude, such as an anode diameter 1420 between about 0.4 mm and about1.0 mm and aperture 1405 diameter ≦about 2.0 mm. Likewise, theaperture-to-eye offset L2 for an embodiment such as shown in FIGS. 56A-E(e.g., incremental retinal beam-spot diameter 1441 i substantiallysmaller than the treated retinal lesion 318) may be comparativelysmaller than for a wider beam radiotherapy treatment plan such as shownin FIGS. 30A-B (e.g., retinal beam-spot diameter similar to the size ofthe treated retinal lesion).

FIG. 56B depicts an example of a schematic frontal view of the centerportion of an eye including limbus 26, iris 24 and a dilated pupil 25providing an enlarged open area (not superimposed on iris) of corneasurface 12. A relatively sparse pattern 312 of cornea entry beam-spots311 (surface spot pattern) comprising n individual beam spots 311 _(i)(where i=1, 2, . . . , n−1, n). In the embodiment shown the patterncomprises narrow beam spots (having a diameter of a small fraction ofthe cornea width) which are spaced apart to permit an area of lower doseor less effected tissue between beam spots, although alternativeembodiments may be employed. In the example shown, the pattern 312 doesnot place beam-spots in the central region of cornea 12, althoughalternative embodiments may include central beam-spots. In one example,the surface spot pattern is arranged in one or more concentric circlesabout the corneal center, as illustrated in FIG. 56B, which alsoindicates the intersection of the eye alignment axis (geometric axis2810) as well as an off-set treatment axis 2820, as described herein.

FIG. 56C depicts a schematic frontal view of the eye as in FIG. 56B,further depicting the underlying surface of retina 1435 as if viewedthrough the cornea and lens (the corneal beam-spot pattern 312 is shownsuperimposed in light, dashed lines). A retinal beam-spot pattern 318 ais shown on the surface of retina 1435, offset and centered on treatmentaxis 2820. As may be seen, in this example, retinal pattern 318 aincludes n individual beam spots 317 _(i), the same number as cornealpattern 312, the retinal beam-spots being shown slightly larger toexemplify beam divergence along the eye tissue path. Note that theretinal pattern 318 a is tight and overlapped, indicating focus of thetarget depth dosage in a relatively small target area. In contrast, thecornea pattern 312 is loose, having space-apart beam-spots, indicatingthe dispersion of the surface dosage over a larger area of tissue,reducing average local dose intensity. Note in the general case, retinalpattern 318 a may have an included area substantially larger any singlebeam-spot 317. However, in an alternative embodiment, the beamspots 317may be superimposed (in the manner of FIG. 30B.

FIG. 56D is a view combining the features of FIGS. 56B and 56C, furtherdepicting n individual X-ray beam paths 1440 _(i), each linearlyconnecting and intersecting a respective patterned corneal beam-spot 311_(i) and target retinal beam-spot 317 _(i). Implied, but not shown inFIG. 56D, are the X-ray anode 1420 and collimator aperture 1405 located(at the sequenced time of beam emission) axially along each of paths1440 _(i).

In on example method of planning a radiotherapy treatment as illustratedin FIGS. 56A-D, the method includes the steps of:

(a) determining X-ray beam parameters of an X-ray source/collimator112-118 as indicated in FIG. 56A, including one or more of energy,filtration, anode size, collimator dimensions L0, L1, and L2, beamduration, and the like, optionally taking into considerationpatient-specific parameters such as disease state, lesion dimensions andlocation, eye size or axial length (≈L3), and the like;

(b) providing an eye model relating X-ray source/collimator geometry toeye geometry;

(c) determining, and including in the eye model, a cornea surfacepattern 312 containing n beam-spots 311 _(i);

(d) determining, and including the eye model, a retinal surface targetpattern 318 a containing n beam-spots 317 _(i);

(e) determining from patterns 312 and 318 a, and including the eyemodel, n treatment beam paths 1440 i;

(f) programming (optionally this may be manually controlled) a roboticX-ray source positioner controller (e.g., processor 501 and positioner115 in FIG. 33A-B) to move through a sequence of n X-ray collimatorlocations/orientations corresponding to the beam paths n treatment beampaths 1440 i determined in step (e);

(g) emitting n sequential treatment beams along paths 1440 i accordingto the parameters determined in step (a), noting that the parameter maybe, but do not need to be, identical for each beam.

(h) optional steps may include, in any operative order, eye alignment,stabilization, tracking, dose mapping and eye motion compensation orgating as described herein with respect to alternative treatment methodsand embodiments.

FIG. 56E depict alternative retinal beam pattern 318 b and 318 c on thesurface of retina 1435, depicting an example where a target lesion isirregular or discontinuous. Thus, the pattern of beam spots 317 i neednot form a circular pattern, or even a single region. Note also theassociated examples of non-circular beam-spots 317′ and 317″,corresponding to a corresponding non-circular collimator aperture 1405(or other beam shaping members, such as adjustable or exchangeableshutters or the like). Alternative retinal pattern configurations suchas shown in FIG. 56E may permit more efficient or limited distributionof dose to the retina, reducing the magnitude of dose applied to otherareas, such as the cornea, lens, or adjacent structures such as theoptic nerve.

Continuous Track/Continuous Motion Stereotactic Treatment.

FIGS. 57A-E depict alternative method and device embodiments havingaspects of the invention, for retinal external-beam radiotherapyemploying one (or more) narrow X-ray beams 1440 such as shown in FIG.56A, whereby the beam may be emitted while X-ray source/collimator112/118 is in motion, the beam being emitted so as to intersect adefined body surface and defined target region track. In the exampledepicted in the figures, the body surface includes the cornea 12 and thetarget region includes retinal surface 1435.

FIG. 57A depicts an example of a schematic frontal view of the centerportion of an eye, which as in FIG. 56B includes limbus 26, iris 24 anda dilated pupil 25 providing an enlarged open area of cornea surface 12.A surface track 313 is defined on cornea 12, in this example formed as aspiral-like shape, proceeding from a initiation point 31 a near thelimbus 26 to a terminal point 313 b. Many other track configurations arepossible, including discontinuous tracks; a plurality of isolated rings,radial paths or the like. FIG. 57A illustrates three examples of beamconfiguration:

(a) In the case of a beam-spot 311 a corresponding to a continuouslymoving beam intersection point formed by, for example, a circularcross-section collimated X-ray beam (e.g., beam 1440 of FIG. 56A), thebeam spot may be represented by an elongated shape or “swath” having awidth representing the collimated beam diameter, and a lengthrepresenting the distance of motion of the intersection point alongsurface track 313 during the duration of emission of radiation.

(b) Where collimator motion is continuous and radiation emission isintermittent or pulsed, the beam-spot may be represented by a sequenceof short “dashed line” spot shapes 311 b.

(c) Where collimator motion is discontinuous and radiation emission iscoordinated on a “start-stop” sequence (fixed position emission), thebeam-spots may be a series of circular shapes 311 c, generallyresembling the pattern of FIG. 56B.

FIG. 57B depicts an example of a schematic frontal view of the eye as inFIG. 57A, further depicting the underlying surface of retina 1435 as ifviewed through the cornea and lens. A retinal surface track 318 a isshown on the surface of retina 1435, generally lying adjacent of atreatment region 318, offset and centered on treatment axis 2820. Anexemplary retinal beam spot 1441 _(i) is shown, but it should be notedthat a corresponding retinal beam spot or swath is implied for each ofthe example cornea entry spots or swaths 311 a, 311 b and 311 c shown inFIG. 57A. It may be noted that where the surface area of corneal pattern313 is substantially larger than the area of the target region 318 (asin preferred embodiments), the beam entry spots or swaths 311 a, b or care in general spaced apart from one another laterally, and in theexample shown avoid the central cornea. In contrast, the retinal beamspots or beam swaths 1441 along retinal track 318 a are shown overlappedlaterally to provide continuous dose distribution in the target region318.

In an embodiment of a method having aspects of the invention as shown inFIGS. 57C and 57D, a point-to-point or segment-to-segment mapping 400 isdefined between each point or segment of cornea track 313 and acorresponding point or segment of retinal track 318 a. Based on mapping400, any desired number of beam paths 1440 i may be defined by linesintersecting a selected point on retinal path 318 a and itscorresponding point on corneal track 313. The segment so definedrepresents the tissue path length L3 for beam 1440 i, and may be nearlyequal to the eye axial length.

Note that as described above with respect to FIGS. 57A-B, a beam path1440 _(i) may be defined independently of whether radiation is emittedalong the path. Thus a given path 1440 _(i) may lie within a beam entrypoint or swath 311 a,b, or c, (and thus being a radiation path) oralternatively may lie within a gap in radiation emission along track 313(a “null” path). For example, a beam path may be defined at thebeginning and at the termination of radiation emission in a swath suchas 311 a, a beam path may be defined to be the initiation point for aradiation pulse of fixed duration 311 b, or may define a halt point fora “stop-start” fixed position beam emission 311 c.

The beam path 1440 i may be extrapolated towards the X-ray anode (orother radiation source, such as a laser output or other optical element;a RF emitter, wave-guide, or the like), in the example shown defining acollimator exit aperture location at distance L2 (collectively aperturetrack 1405 a), and defining an anode location at a further distance L1(collectively anode track 1420 a). Note that for non-refracted ornon-reflected photons such as X-rays, the radiation source geometry maybe modeled shown in FIG. 21. For other treatment modalities, such aslaser treatment, RF treatment and the like, models may be mostconveniently take into account particular components for those sources,such as lenses, mirrors, slits, waveguides, and the like.

For orthovoltage X-ray treatment systems described in detail herein, thelengths L1, L2, and L3 (and their sum L0) need not be constant for eachbeam path 1440 i, although in certain embodiments, these dimensions maybe approximately constant.

(1) For a fixed collimator geometry, L1 will be constant. However, asshown in FIGS. 28 and 58, collimator embodiments having aspects of theinvention may have variable geometry, such a telescoping exit apertureposition, aperture or collimator rotation (e.g., for asymmetrical oroffset apertures), and aperture lateral motion in one or two dimensions.Alternatively, the collimator aperture 1405 may have a variablediameter. In yet other embodiments, the radiation system may includeadditional beam shaping elements, such as separately positionableshields, lenses (e.g., in laser treatments), and the like.

(2) L2, the distance from collimator exit to eye or other body surface,the distance may be selected to be constant. Alternatively, the distancemay be varied, such as to modify penumbra size, or to adjust the overallanode-to-target distance L0 for different tissue path lengths L3.

(3) Depending on cornea contour, eye shape and size, the shape andlocation of the target lesion, and the configuration of the cornea track313, the tissue path length L3 may vary modestly, but may beapproximately constant.

Thus in the example method, each identified or selected point or segmentp3 of retinal track 318 a corresponds to three other defined points: p2(cornea), p1 (aperture), and p0 (anode). These locations may beautomatically computed based on computer eye/system model (or may bedetermined manually), and the data stored, for example by suitablesoftware and memory devices of system processor 501 as shown in FIG.33B. The anode-aperture points p0, p1 define a line segment indicating aposition and orientation of X-ray source assembly 420 corresponding tothe particular beam path 1440 i.

As may be seen, collectively the defined points p0, p1 of successivebeam paths 1440 i define a track followed by the anode 1420 a and atrack followed by the aperture 1405 a corresponding to the corneal track313 and the retinal track 318 a. Likewise, the velocity of progressionof the treatment system along its respective tracks, such as bytranslation and/or rotation of X-ray tube/collimator 112/118, in turndefine a velocity of progression of the emitted X-ray beam (or “null”beam for tube “off”) at the corneal surface track 313 and the retinaltrack 318 a. These velocities may be constant, or may be selected tovary according to a chosen velocity profile. Similarly, X-ray emissionmay be selected to be triggered or stopped at selected locations basedon system position, or at selected times during system movement, e.g.,based on system velocity. A robotic X-ray source positioner (e.g.,positioner 115 controlled by processor 501) may be programmed with themodeled data as described above to carry out a particular plannedradiation treatment.

A number of strategies may be used to provide a selected total doseprofile within the target region (e.g., a generally uniform “table top”dose over region 318 with a sharp fall off at its edgy, see FIG. 28). Inthe example depicted in FIGS. 57A-D, the shape and spacing of thecorneal track 313 and the retinal track 318 a may be configured toprovide an approximately uniform dose profile across target region 318when the system progresses along track 318 a at constant velocity withconstant X-ray emission at a constant energy spectrum and collimationparameters (continuous beam swath 311 a).

Alternatively or in combination, the system may be programmed toprogress along retinal track 318 a at a variable velocity, so as toadjust dose application (integral of intensity and time) to be uniformwith respect to area of region 318, taking into account the areas ofoverlap of adjacent loops of the spiral shape of track 318 a. In yetfurther alternatives, the collimator or source parameters may be variedduring beam progression (L2, L1 and/or L0, photon maximum energy,variable filtration, adjustable aperture diameter, and the like) so asto adjust dosage distribution within target region 318.

In the example shown in FIGS. 57A-D, the retinal track 318 a isconfigured as a spiral form generally filling a circular target region318. In alternative embodiments, target region 318 may be noncircular,irregular or discontinuous. FIG. 57E depicts two examples ofalternatively configured retinal tracks: track 318 b of spiral-likeform, configured to fill a elliptical target region 318; and track 318 cconfigured to be non-spiral in character and delimited to fill the shapeof the irregular target 318.

In an exemplary alternative embodiment shown in FIG. 57F, both cornealtrack pattern 313′ and retinal track pattern 318 d may be arranged as aseries of n short track segments 311 _(i) and 1441 _(i) respectively aremay be spaced apart to converge along radial lines emanating from thecenter 2820 of target region 318, which may be centered on a treatmentaxis 2820. In the example 313′ shown, n=24 and the tracks are arrangedat 15 deg. angles on radii about target center 2820. The geometry of thetracks 313′ and 318 d are selected so that the beam swaths 1441 i ontarget region 318 overlap and provide continuous dose application.

The starting and stopping points of segments 311 _(i) and 1441 _(i) maycorrespond to the beginning and ending of the motion of an externalradiation beam source. Alternatively, the initiation or terminationpoints of treatment radiation even while a physical source continues tobe moved or re-oriented in the direction of the track. Examples includeon-off switching of a laser source being moveably oriented by mirrordeflection; open/close state of a radio-opaque shutter isolating anisotope; and the startup/shutdown of the power supply or bias grid of anX-ray tube being translated and/or rotated by an automated positioner(tube 112 by positioner 115 in FIG. 33). In yet other alternatives, theradiation beam may reverse direction and move back over all or a portionof the track extent (within the track and/or at track endpoints).

In alternative embodiments, the individual track segments 311 _(i) and1441 _(i) need not be straight line segments and need not progressradially inward. Likewise the segments do not need to be similarlyshaped or delimited by constant radii with respect to the cornealcenter. Also shown in FIG. 57F is an examples of corneal track 313″ inwhich the segments are arranged as nested curves progressing outward,and corneal track 313′″ in which the track is generally circumferential.Similarly, although example corneal track 313′-313′″ avoid the centerregion of cornea 12, although alternative embodiments may includecentral beam-spots.

FIGS. 57G,H are a frontal view and corresponding cross-section of an eye30, showing in greater detail the example of the corneal track pattern313′ and retinal track pattern 318 d of FIG. 57F. The corneal tracksegments 311 _(i) may be delimited by defining starting and stoppingpoints, such as on intersection of the track with two concentriccircles, in this example centered on the geometric axis 2810 of the eye.The retinal track segments are delimited 1441 _(i) similarly by astarting point adjacent the edge of circular target region 318 andstopping point adjacent the treatment axis 2820. Note in this examplethe incremental track segments 311 _(i) and 1441 _(i), do not haveidentical length even though they are delimited by concentric circlesabout eye geometric axis 2810, because the segments are orientedradially about a treatment axis 2820, which in the general case may beoffset from geometric axis 2810. In this example, the X, Y and Z axesare for convenience defined with respect to the off-set treatment axis2820.

In FIGS. 57G-H, two example corneal incremental track segments aredepicted, indicated as 311 i, 311 j, along with their correspondingretinal track segments 1441 i and 1441 j (as dashed lined areas). Thecross section of FIG. 57H shows the respective beam paths 1440 i and1440 j, intersecting the respective corneal track (indicated assuspended arrows) at the cornea surface 12; then propagating at an angleto the treatment axis (Φ_(0,i), and Φ_(0,j), respectively) so as tointersect the retina surface 1435 within target region 318. The cornealand retinal tracks in this example are so arranged that none of the beampaths 1440 _(i) passes through or near optic nerve 32. In addition, thecorneal and retinal tracks may be arranged to take into account anysecondary effects that the particular radiation spectrum and doseemployed (e.g., visible light, IR, UV, RF, isotope decay species, X-ray,or the like) may have on corneal or lens tissue, such as alteration ofrefractive shape or transparency, so as to minimize any adverse effects.

In this example, the corneal and retinal tracks are defined as lyingwithin parallel corneal and retinal tangent planes 12 a, 1435 a (heavy,solid arrows) positioned closely adjacent the respective corneal andretinal surfaces 12, 1435 respectively, with very little cumulativeerror. Alternatively, the tracks may be defined as parallel to therespective tissue surfaces, such as lying on, near or within the actualtissue surface (light, dashed arrows).

Note also from FIGS. 57F-H that due to the radial arrangement of bothtracks 313′ and 318 d, in the particular case where both retina 1435 andcornea 12 may be approximated with sufficient accuracy as parallelplanes, the X-ray tube/collimator assembly 112/118 may progress to movethe beam along each segment 1441 _(i) solely by translation in a planeperpendicular to the treatment axis 2820 (X-Y plane), and withoutrotation (Φ or θ) or motion in the axial direction (Z) during radiationemission.

In the example shown, the respective corneal track and retinal tracksegments (311 i/1441 i) are linear, parallel and equal length (this neednot be so). In this case, the collimator angle Φ for each may be heldconstant within the track segment (Φ_(0,i)), and the collimator may bemoved only in linear translation in the XY plane (indicated as dx,dx) toaccomplish progression of beam 1440 i over the length of the segments.Such constrained and limited degree of freedom motion, as in otherembodiments described herein, promotes accuracy and precision ofactuator performance and consequently more predictable radiation doseapplication to tissue.

However, note that in the example shown due to the offset position oftarget 318, the angle although Φ₀ varies from segment to segment, theexamples 311 i, 311 j shown being relatively extreme examples arrangedon opposite sides of off-set target 318, so that the angle is muchlarger for the left-hand beam Φ_(0,i) than the right hand beam Φ_(0,j).Movement between successive track segments 1441′ may be by adjustment ofθ (15 deg. increments are shown), and with small adjustments of X, Yand/or Φ to align the beam 1441 _(i) prior to the next increment ofradiation emission (see embodiment of FIGS. 58A-C in this regard).

Furthermore, by adjustment of the velocity of beam progression (e.g., anacceleration profile of collimator 118 as the track progresses radiallyinward), the integrated dose distribution may be provided to be greaternear the beginning of each segment than near the end of the segment(gradient-dose segment). The overlapped segments 1441 (i from 1 to n)may be configured in dose gradient to provide, in cumulative effect, asubstantially uniform dose over target region 318.

Beam Configuration Control and Actuation Via Movable CollimatorElements.

FIGS. 58A-C and also FIG. 28 depict embodiments of collimator assemblies118 which comprise additional actuators and movable elements configuredfor rapid and precise motion (e.g., small-range “Vernier actuators”) inaddition to primary radiation source positioning actuators (e.g., asshown in FIG. 37 for one or more of the X, Y, Z, and/or Φ system axes).These are described further in co-invented U.S. Application No.61/093,092 filed Aug. 29, 2008, which is incorporated herein byreference. In this application, the embodiments shown in FIGS. 58A-C aredescribed with respect to methods of tracking eye motion, calculatingthe motion of selected eye structures (e.g., a retinal target and/or avulnerable tissue) base on eye motion signals, and repositioning and/orreorienting an X-ray or other radiation beam source on a real-time basisto compensate for such eye motion.

Independently or in combination with eye motion compensation and otherembodiments herein, the embodiments of FIGS. 58A-C and FIG. 28 havingaspects of the invention are also useful for rapid and precise motioncontrol (or beam parameter control, such as penumbra size) as aradiation beam is emitted for treatment in any of the corneal-entrymethod and device embodiments shown in FIGS. 55-57 herein.

The examples of FIGS. 58A-C and FIG. 28 comprise an orthovoltage X-raysource 112, and describes an example including scleral beam entry spots(see FIG. 43E for example), but the devices and methods are useful forother types of collimated radiation beams and for other targetingmethods described herein as well. In particular, these embodimentprovide a means of moving a radiation beam between incremental beampaths 311 as shown in FIGS. 55 and 56, and for moving a radiation beamalong a continuous beam track or segment, or re-positioning betweenadjacent beam segments, as shown in FIGS. 57A-H.

In the example shown in FIGS. 58 A-C, one or more additional degrees offreedom are provided for structure to move the retinal beam-spotrelative to the initial beam axis 1400. Advantageously, the X-ray sourcemass (weight and inertia) which must be moved for fine scalere-orientation of the beam may be reduced by having an actuatorconfigured to reorient only a portion of the collimator assemblystructure 118 to delimit the beam to a slightly adjusted beam path. Inthe example shown, only a very small fraction of the mass of the X-raysource assembly need be moved to make small compensatory movements ofthe retinal beam-spot, where one or more actuators 119 a are configuredto engage and move a collimator exit aperture plate 1405 b of modestmass, the actuator assembly 118 b being arranged adjacent the distal endof collimator assembly 118. Typically, a small mass may be repositionedmore responsively and accurately than a relatively large mass, such asthe total mass of X-ray source tube 112.

As shown in FIGS. 58A-C, aperture plate 1405 is supported by aperturemounting 119 b (e.g., may be held in position by holders 119 c) andengaged by actuators 119 a. In the example shown, the plate is supportedto move in two dimensions (directions I and J for relative motion di anddj respectively) in a plane perpendicular to the beam axis 1400, butthis need not be so. Similarly, the example depicts pairs of linearactuators in a parallel “push-pull” arrangement for each direction, butthis is purely exemplary. For example, the actuator assembly 118 b mayalternatively provide a rotational degree of freedom (not shown) inaddition to a lateral translation of plate 1405 b, so as to providemotion via polar coordinates lateral to axis 1400.

FIG. 58A provides a cross-sectional “ray-tracing” beam model similar tothat of FIG. 21, with elements generally identified by the samenumerals, and having collimator dimensions similarly identified as L0,L1, L2 and L3. X-ray tube 112 emits a beam 1400 via collimator 118 topropagate to sclera surface 1430, penetrating to retinal surface 1435 toform retinal beam spot 1441. Lateral motion of aperture plate 1405 bmoves the exit aperture 1405 through a distance indicated as aperturetravel 1406. Both the aperture plate 1405 b and the beam 1400 is shownboth in an initial position/orientation (dashed or light lines) and ashifted position/orientation (solid or dark lines) as beam 1400′.

FIGS. 58B and C are frontal elevations of collimator 118, showing thearrangement of linear actuators 119 c to plate 1405 b, wherein figure Brepresents an initial position, and C represents a shifted position,where the plate 1405 b has moved in two directions (di, djrespectively).

Because plate 1405 b is mounted at a distance between anode 1420 andretina 1435, the aperture travel 1406 results in a respective retinalbeam spot travel 1407 which is magnified to a degree. For example, ifaperture 1405 is exactly at the midpoint (L0=2*L1), the beam-spot travel1407 will be twice the aperture travel 1406. Thus a movement of 1 mm byplate 1405 b would in this case result in a shift of approximately 2 mmin beam-spot 1441. Note that retinal motion of a restrained patient maybe on the order of 1-2 mm or less over reasonable treatment periods. Forembodiments in which the aperture is close to sclera surface 1430, themagnification of motion may be modest.

In one alternative, the actuators 119 b comprise one or moreelectromechanical actuators known in the art. In another alternative,the actuators 119 b comprise one or more piezoelectric actuators, suchas a 2-D a piezoelectric actuator stage. Such actuators may beconfigured to controllably translate rapidly (e.g., millisecond orderresponse) over a distance a few mm with accuracy on the order of a fewmicrons.

Note from FIG. 58A that the entry point 311 of beam 1400 at sclera 1430is shifted by a distance comparable to beam-spot travel 1407. In thetreatment systems described herein and in incorporated U.S. ApplicationNo. 61/093,092, the relationship of sclera beam-spot 311 may be activelytracked by imaging system and processors, and accurately predicted basedon eye motion detection. The collimator assembly 118 may include asteerable mirror 1220′ (see laser beacon 1410 and mirror 1220 in FIG.36) to permit a beam-aligned laser beacon to be steered to remainaligned with beam 1400′, so as to assist in automated or operatormonitoring of beam shift. System processors may be configured (e.g., bysuitable software) to predict motion sclera beam-spot 311 so as to avoidmotion of plate 1405 b which would bring the sclera beam-spot 311 withina selected threshold distance of a vulnerable structure, such as thecornea or the lens of the eye (e.g., source-gating could be used tocontrol retinal dose distribution in this case). In many cases, themotion of spot 311 will be away from or at least not towards avulnerable structure.

Alternative Eye-Guide Embodiments Configured for Intra-Ocular Imaging.

FIGS. 59A-D illustrate an eye-guide device 110 for use in a eyestabilizing system having aspects of the invention, the guide having awidow or transparent portion 300 permitting retinal imaging duringtreatment (note alternative example in FIGS. 42C-D). In the exampleshown, the lens 120 is supported by one or more posts or extensions 222,which engage a Y-shaped yoke 190 comprising arms 191, 192. Yoke 190 ismounted to support arm 180 by a swivel 223. Arms 191-192 mount toextensions 222 by means of pivots 224. Pivots 224 and swivel 223 providefreedom of motion for lens 120 two perpendicular directions. Window 300is formed in the center of lens 120 (which may be entirely transparent),so as to permit an image to be obtained from the interior of eye 130while eye-guide 110 is engage to the eye. Vacuum connection 275communicates off-center on lens 120 and does not obstruct window 300.

FIGS. 60A-D illustrate an alternative eye-guide device 110 for use in aeye stabilizing system having aspects of the invention, similar in manyrespects to the embodiment shown in FIGS. 59A-D. As in the eye-guide ofFIG. 59, the guide has a widow or transparent portion permitting retinalimaging during treatment, and has a vacuum line to provide suction atthe lens contact surface. In this example, the lens 120 is supported bya frame comprising a first jointed post 225 b linked to the end ofsupport arm 180, and by a second jointed post 225 a via tie rod 226 andattachment 227 to a medial portion of support arm 180. The arrangementof these components forms a generally quadrilateral frame, which may bemade adjustable by an adjustment mechanism, in this case the tie barbeing jointed to a slide-and-set screw assembly 227, which may beselectively repositioned along the axis of the support arm 180. Thearrangement shown permits the eye-guide 110 to have asymmetric pivotingcharacteristics, whereby pivot resistance may be selected to bedifferent is the X and Y directions.

FIG. 60E illustrates an alternative embodiment similar to that of FIGS.60A-D, in which the support frame for lens 120 is rotated approximately90 deg. with respect to the support arm 180, so that the lens 120 is atthe end of a moment arm about the axis of the support arm 180. Themoment arm permits a bias or reaction force of the lens 120 upon eye 30to be transmitted as a torque about the support arm 180. This may beexploited or regulated by means of a torque spring or other actuatorwithin eye guide support (600 in FIG. 40).

From the foregoing, it can be seen how various objects and features ofthe invention are met. While certain aspects and embodiments of thedisclosure have been described, these have been presented by way ofexample only, and are not intended to limit the scope of the disclosure.The methods and systems described herein may be embodied in a variety ofother forms without departing from the spirit thereof. All publicationsand patents cited herein are expressly incorporated herein by referencefor the purpose of describing and disclosing systems and methodologieswhich might be used in connection with the invention.

It is claimed:
 1. A treatment planning method for treating maculardegeneration in a patient, comprising: scaling, to a measured oculardimension of an eye, a model of the eye that includes coordinates ofretinal features, including a macula and a virtual ocular medium;establishing at least two treatment axes along which a collimated beamof X-radiation is directable from an external radiation source at themacula in the eye model; determining, from the known distance of travelof the beam within the model along each treatment axis and from thevirtual ocular medium through which the beam travels, the dose ofradiation from the source that needs to be delivered along eachtreatment axis to produce a predetermined total radiation dose at themacula of the eye; and directing collimated X-radiation beams at themacula in the eye.
 2. The method of claim 1, wherein scaling the modelincludes measuring along an ocular axis, the ocular length of thepatient's eye between the cornea and retina of the eye, and scaling theocular length of the model to the patient's measured ocular length. 3.The method of claim 1, wherein establishing the at least two treatmentaxes includes establishing at least three treatment axes directedthrough the sclera and converging at the macula in the eye model, andhaving a total beam-to-beam angular divergence of between 20-60 degrees.4. The method of claim 1, wherein the eye model includes coordinates ofthe optic nerve at the retina, the dose of radiation is determined asspecified beam intensity over a given irradiation period, and thedetermining the dose further includes determining a permitted extent ofeye movement over the irradiation period that maintains the radiationdose received at the patient optic nerve below a predetermined level. 5.The method of claim 1, wherein directing collimated X-radiation beamscomprises producing the predetermined total radiation dose at the maculaof the eye.
 6. Non-transitory machine-readable medium which operateswith a computer to execute machine-readable instructions for treatingmacular degeneration in a patient, comprising the steps of: scaling, toa patient-eye ocular dimension supplied as input, a model of an eye thatrepresents retinal features, including the macula and a virtual ocularmedium; establishing at least two treatment axes along which acollimated beam of X-radiation will be directed from an externalradiation source at the macula in the eye model; determining from aknown distance of travel of the beam within the model along eachtreatment axis and from the virtual ocular medium through which the beamtravels, the dose of radiation from the source that needs to bedelivered along each treatment axis to produce a predetermined totalradiation dose at the macula of the eye; and directing collimatedX-radiation beams at the macula in the eye.
 7. The non-transitorymachine-readable medium of claim 6, wherein directing collimatedX-radiation beams comprises producing the predetermined total radiationdose at the macula of the eye.